Chiral N-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof

ABSTRACT

The present invention relates to novel compounds of Formula I and their use in therapeutic treatments. The invention further relates to a novel chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines using N-sp3 protective groups. The invention also provides intermediates for use in the synthesis of compounds of Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.14/349,595, filed Apr. 3, 2014, which application is a 35 U.S.C. § 371National Phase Application of International PCT Patent Application No.PCT/EP2012/0069546, filed Oct. 3, 2012, which application claimspriority to European Patent Application Serial Nos. EP 11183678.9, filedOct. 3, 2011, EP11183692.0, filed Oct. 3, 2011, EP 11183681.3, filedOct. 3, 2011, EP 11183679.7, filed Oct. 3, 2011, and U.S. ProvisionalPatent Application No. 61/543,611, filed Oct. 5, 2011, the contents ofeach of which are incorporated herein by reference in their entireties.

FIELD OF INVENTION

The present invention relates to novelN-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinesincluding their pharmaceutically acceptable salts and solvates that areselective antagonists to neurokinin-3 receptor (NK-3) and are useful astherapeutic compounds, particularly in the treatment and/or preventionof a broad array of CNS and peripheral diseases or disorders.

The present invention also relates to a novel chiral synthesis of5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineintermediates for use in the synthesis of pharmaceutical activeingredients, such as selective antagonists to the neurokinin 3 receptor(NK-3), especially theN-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinesof the invention. The invention also pertains to novelstereoisomerically pure5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineintermediates obtained by the chiral synthesis of the invention as wellas to novel intermediates of this synthesis.

BACKGROUND OF INVENTION

Tachykinin receptors are the targets of a family of structurally relatedpeptides which include substance P (SP), neurokinin A (NKA) andneurokinin B (NKB), named collectively “tachykinins”. Tachykinins aresynthesized in the central nervous system (CNS) and peripheral tissues,where they exert a variety of biological activities. Three tachykininreceptors are known which are named neurokinin-1 (NK-1), neurokinin-2(NK-2) and neurokinin-3 (NK-3) receptors. Tachykinin receptors belong tothe rhodopsin-like seven membrane G-protein coupled receptors. SP hasthe highest affinity and is believed to be the endogenous ligand ofNK-1, NKA for NK-2 receptor and NKB for NK-3 receptor, althoughcross-reactivity amongst these ligands does exist. The NK-1, NK-2 andNK-3 receptors have been identified in different species. NK-1 and NK-2receptors are expressed in a wide variety of peripheral tissues and NK-1receptors are also expressed in the CNS; whereas NK-3 receptors areprimarily expressed in the CNS.

The neurokinin receptors mediate a variety of tachykinin-stimulatedbiological effects that include transmission of excitatory neuronalsignals in the CNS and periphery (e.g. pain), modulation of smoothmuscle contractile activity, modulation of immune and inflammatoryresponses, induction of hypotensive effects via dilatation of theperipheral vasculature and stimulation of endocrine and exocrine glandsecretions.

In the CNS, the NK-3 receptor is expressed in regions including themedial prefrontal cortex, the hippocampus, the thalamus and theamygdala. Moreover, NK-3 receptors are expressed on dopaminergicneurons. Activation of NK-3 receptors has been shown to modulatedopamine, acetylcholine and serotonin release suggesting a therapeuticutility for NK-3 receptor modulators for the treatment of a variety ofdisorders including psychotic disorders, anxiety, depression,schizophrenia as well as obesity, pain or inflammation (Exp. OpinionTher. Patents (2000), 10(6), 939-960; Current Opinion in InvestigationalDrugs, 2001, 2(7), 950-956 and Current Pharmaceutical Design, 2010, 16,344-357).

Schizophrenia is classified into subgroups. The paranoid type ischaracterized by delusions and hallucinations and absence of thoughtdisorder, disorganized behavior, and affective flattening. In thedisorganized type, which is also named ‘hebephrenic schizophrenia’ inthe International Classification of Diseases (ICD), thought disorder andflat affect are present together. In the catatonic type, prominentpsychomotor disturbances are evident, and symptoms may include catatonicstupor and waxy flexibility. In the undifferentiated type, psychoticsymptoms are present but the criteria for paranoid, disorganized, orcatatonic types have not been met. The symptoms of schizophrenianormally manifest themselves in three broad categories, i.e. positive,negative and cognitive symptoms. Positive symptoms are those, whichrepresent an “excess” of normal experiences, such as hallucinations anddelusions. Negative symptoms are those where the patient suffers from alack of normal experiences, such as anhedonia and lack of socialinteraction. The cognitive symptoms relate to cognitive impairment inschizophrenics, such as a lack of sustained attention and deficits indecision making. The current antipsychotic drugs (APDs) are fairlysuccessful in treating the positive symptoms but fare less well for thenegative and cognitive symptoms. Contrary to that, NK3 antagonists havebeen shown clinically to improve on both positive and negative symptomsin schizophrenics (Meltzer et al, Am. J. Psychiatry, 161, 975-984, 2004)and ameliorate cognitive behavior of schizophrenics (Curr. Opion.Invest. Drug, 6, 717-721, 2005).

In rat, morphological studies provide evidence for putative interactionsbetween NKB neurons and the hypothalamic reproductive axis (Krajewski etal, J. Comp. Neurol., 489(3), 372-386, 2005). In arcuate nucleusneurons, NKB expression co-localizes with estrogen receptor α anddynorphin, implicated in progesterone feedback to Gonadotropin ReleasingHormone (GnRH) secretion (Burke et al., J. Comp. Neurol., 498(5),712-726, 2006; Goodman et al., Endocrinology, 145, 2959-2967, 2004).Moreover, NK-3 receptor is highly expressed in the hypothalamic arcuatenucleus in neurons which are involved in the regulation of GnRH release.

WO 00/43008 discloses a method of suppressing gonadotropin and/orandrogen production with specific NK-3 receptor antagonists. Moreparticularly, the WO 00/43008 application relates to loweringluteinizing hormone (LH) blood level by administering an NK-3 receptorantagonist. Concurrently or alternatively with gonadotropin suppression,WO 00/43008 also relates to suppression of androgen production with NK-3receptor antagonists. Recently it has been postulated that NKB actsautosynaptically on kisspeptin neurons in the arcuate nucleus tosynchronize and shape the pulsatile secretion of kisspeptin and drivethe release of GnRH from fibers in the median eminence (Navarro et al.,J. of Neuroscience, 23, 2009-pp 11859-11866). All these observationssuggest a therapeutic utility for NK-3 receptor modulators for sexhormone-dependent diseases.

Non-peptide ligands have been developed for each of the tachykininreceptors. Some of them have been described as dual modulators able tomodulate both NK-2 and NK-3 receptors (WO 06/120478). However, knownnon-peptide NK-3 receptor antagonists suffer from a number of drawbacks,notably poor safety profile and limited CNS penetrability that may limitthe success of these compounds in clinical development.

On this basis, new potent and selective antagonists of NK-3 receptor maybe of therapeutic value for the preparation of drugs useful in thetreatment and/or prevention of CNS and peripheral diseases or disordersin which NKB and the NK-3 receptors are involved.

Antagonists to Neurokinin-3 Receptor (NK-3)

The invention thus encompasses compounds of general Formula I, theirpharmaceutically acceptable salts and solvates as well as methods of useof such compounds or compositions comprising such compounds asantagonists to the NK-3 receptor. Compounds of Formula I areN-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines.The compounds of the invention are generally disclosed in internationalpatent application PCT/EP2011/055218 but none is specificallyexemplified therein.

In a general aspect, the invention provides compounds of general FormulaI:

and pharmaceutically acceptable salts and solvates thereof, whereinAr¹ is unsubstituted thiophen-2-yl, unsubstituted phenyl, or4-fluorophenyl;R¹ is H or methyl;Ar² is of general Formula (i), (ii) or (iii):

-   -   wherein    -   R² is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or        branched C2-C3 alkenyl, C3-C4 cycloalkyl or di(C1-C2        alkyl)amino;    -   X¹ is N or C—R⁶ wherein R⁶ is H, fluoro or C1-C2 alkyl;    -   X² is O or S;    -   X³ is N, or X³ is CH under the condition that X¹ is N and X² is        N—R⁷ wherein R⁷ is linear or branched C1-C3 alkyl or        cyclopropyl;    -   R³ is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl;    -   X⁴ is N or C—R⁸ wherein R⁸ is H or C1-C2 alkyl;    -   X⁵ is O or S;    -   X⁶ is N, or X⁶ is CH under the condition that X⁴ is N and X⁵ is        N—R⁹ wherein R⁹ is linear or branched C1-C3 alkyl or        cyclopropyl;    -   R⁴ is halo, cyano, methyl, or hydroxyl;    -   R⁵ is H or halo;        with the condition that when Ar² is of Formula (iii), then R¹ is        methyl; and the compound of Formula I is not

-   (3-(2-isobutylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7    (8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;

-   [1,1′-biphenyl]-4-yl(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

-   (8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising at least one compound according to the inventionor a pharmaceutically acceptable salts or solvate thereof.

The invention also relates to the use of the above compounds or theirpharmaceutically acceptable salts and solvates as modulators of NK-3receptors, preferably as antagonists of NK-3 receptors.

The invention further provides methods of treatment and/or prevention ofdepression, anxiety, pyschosis, schizophrenia, psychotic disorders,bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer'sdisease, attention deficit hyperactivity disorder (ADHD), pain,convulsion, obesity, inflammatory diseases including irritable bowelsyndrome and inflammatory bowel disorders, emesis, pre-eclampsia, airwayrelated diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders, contraception and sex hormone-dependent diseasesincluding but not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carninoma, testicularcancer, breast cancer, ovarian cancer, androgen dependent acne, malepattern baldness, endometriosis, abnormal puberty, uterine fibrosis,uterine fibroid tumor, hormone-dependent cancers, hyperandrogenism,hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrualdysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulinresistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-ANwith hyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosiscomprising the administration of a therapeutically effective amount of acompound or pharmaceutically acceptable salts or solvate of Formula I,to a patient in need thereof. Preferably the patient is a warm-bloodedanimal, more preferably a human.

The invention further provides methods of treatment for gynecologicaldisorders and infertility. In particular, the invention provides methodsto suppress the LH-surge in assisted conception comprising theadministration of a therapeutically effective amount of a compound orpharmaceutically acceptable salts or solvate of Formula I, to a patientin need thereof. Preferably the patient is a warm-blooded animal, morepreferably a woman.

The invention further provides methods to affect androgen production tocause male castration and to inhibit the sex drive in male sexualoffenders comprising the administration of a therapeutically effectiveamount of a compound or pharmaceutically acceptable salts or solvate ofFormula I, to a patient in need thereof. Preferably the patient is awarm-blooded animal, more preferably a man.

The invention also provides the use of a compound of Formula I or apharmaceutically acceptable salts or solvate thereof as a medicament.Preferably, the medicament is used for the treatment and/or preventionof depression, anxiety, pyschosis, schizophrenia, psychotic disorders,bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer'sdisease, attention deficit hyperactivity disorder (ADHD), pain,convulsion, obesity, inflammatory diseases including irritable bowelsyndrome and inflammatory bowel disorders, emesis, pre-eclampsia, airwayrelated diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders, contraception and sex hormone-dependent diseasesincluding but not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carninoma, testicularcancer, breast cancer, ovarian cancer, androgen dependent acne, malepattern baldness, endometriosis, abnormal puberty, uterine fibrosis,uterine fibroid tumor, hormone-dependent cancers, hyperandrogenism,hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrualdysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulinresistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-ANwith hyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis. Themedicament may also be used for the treatment of gynecologic disorders,infertility and to affect androgen production to cause male castration.

Chiral Synthesis of5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineCompounds

TheN-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineof general Formula I of the invention can be prepared by different wayswith reactions known to a person skilled in the art.

The Applicant further proposes therein a new chiral synthesis for thecompounds of the invention and especially for(R)-8-substituted-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineintermediatesthat may be converted into compounds of Formula I by N-acvlation.

Different synthetic approaches that are of general relevance to thesynthesis of(R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine are knownin the literature. The below examples and experimental conditions ofrelevant approaches provided are illustrative only.

In Method A(i) (see Scheme A), the [1,2,4]triazolopyrazine core IIIa(i)is formed by acetylation of 2-hydrazidopyrazine (step 1) followed by acyclodehydration reaction (step 2), using procedures familiar to thoseskilled in the art. This methodology was initially developed by Nelsonand Potts (J. Org. Chem. 1962, 27, 3243-3248). Subsequent reduction ofthe pyrazine ring with H₂/Pd affords the[1,2,4]triazolo[4,3-a]piperazine (step 3). This method is well describedin the literature and has been used, for example, in the Merck synthesisof Sitagliptin (Hansen, K. B. et al. Org. Process Res. Dev. 2005, 9,634-639 and references therein). However, i) perusal of the existingliterature indicates that this procedure is generally used withsubstrates wherein R¹═H (i.e. non-chiral analogs, cf. Scheme A), and ii)that the application of this method to prepare chiral[1,2,4]triazolo[4,3-a]piperazine variant of general Formula IVa(i) (inMethod A(i)) has not been disclosed. The dearth of examples of pyrazinesubstrates wherein R¹≠H in this methodology may be due to the difficultyof pyrazine reduction step; noteworthy in this regard is the fact thatin the optimized process scale-up procedure reported by Hansen et al.,the pyrazine (R¹═H) reduction (step 3, Scheme A) proceeded in merely 51%yield. In addition to the issue of chemical yield, access to chiralsubstrates through reduction of [1,2,4]triazolopyrazine substrateswherein R¹≠H would require the additional challenge of efficientasymmetric hydrogenation conditions (in terms of both yield and chiralpurity); this is currently not a known procedure to the best ofApplicant's knowledge. Thus application of Method A(i) for chiralsynthesis of [1,2,4]triazolo[4,3-a]piperazine structures is hithertounknown.

Method A(ii) (cf. Scheme B) is a variation on Method A(i) whereby thereduction of R¹≠H substituted [1,2,4]triazolopyrazine substrates iscircumvented. This method has been reported by the Merck group in theirstudies related to Sitagliptin (see, for example, Kowalchick, J. E. etal. Bioorg. Med. Chem. Lett. 2007, 17, 5934-5939), wherein Boc-protectedintermediates depicted by general Formula IVa(ii) are deprotonated witha strong base, such as n-butyllithium, in the presence oftetramethylethylenediamine (TMEDA), followed by treatment of the thusgenerated anion with an electrophile such as an alkyl halide (step 4,Scheme B). The chiral variant of this methodology has not been reportedin the literature.

Inspired by the earlier work by Makino and Kato (JP016128261(A), 1994),yet another alternative approach to the synthesis of[1,2,4]triazolo[4,3-a]piperazines was developed usingchloromethyloxadiazoles as a key reagent (Balsells, J. et al. Org. Lett.2005, 7, 1039-1042). This methodology (Method B) is depicted in Scheme Cbelow. As reported by Balsells et al., however, this approach proceedsin high yield mainly when the strong electron-withdrawing R₂═CF₃ groupis present in the chloromethyloxadiazole reagent. In addition, themechanism suggested by the said authors would render application of thisstrategy unlikely, if not impossible, for a chiral synthesis of IVbintermediates (cf. Scheme C). Indeed, in the current literature onlyracemic or achiral products are described using such an approach. Thus,application of Method B towards preparation of chiral[1,2,4]triazolo[4,3-a]piperazine structures has never been disclosed.

Another well-known method for the preparation of[1,2,4]triazolo[4,3-a]piperazine containing structures is shown inScheme D below (Method C). Addition of acetylhydrazide topiperazinoimidate (step 1) is followed by cyclodehydration to form thefused triazolo ring (step 2). This method is well documented in theliterature although exemplified only through racemic or achiralstructures; e.g.: McCort, G. A.; Pascal, J. C. Tetrahedron Lett., 1992,33, 4443-4446; Brockunier, L. L. et al. WO 03/082817 A2; Chu-Moyer, M.Y. et al. U.S. Pat. No. 6,414,149 B1; Banka, A. et al. WO2009/089462 A1.To the best of his knowledge, the Applicant is unaware of any publishedreports of the application of this method for obtaining chiral productsby starting from chiral piperazinones (Id in Scheme D).

A synthesis of(R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine compoundsthrough general Method C has been previously described in internationalpatent application PCT/EP2011/055218 which is in the name of theApplicant. The preparation disclosed therein is depicted in Scheme E:

Boc-protected ketopiperazine lie was prepared and then converted toiminoether IIIe by using the Meerwein reagent (e.g. Et₃OBF₄).Cyclodehydration reaction between the acyl hydrazide IVe and theiminoether aforementioned was conducted either under forcing thermalreflux conditions, or by applying excessive microwave irradiation in asealed tube typically for rather protracted reaction times (often days).When using microwave irradiation, N-Boc deprotection occurred during thesaid cyclodehydration step; thus, a deprotection step was typically notnecessary to conduct (i.e., IIIe+IVe→VIein Scheme E). However, whenthermal cyclodehydration conditions were applied, Boc-deprotection stepwas required (i.e., IIIe+IV→Ve→VIe).

As noted in Scheme E above, steps 2 and 3 have shortcomings thatsignificantly limit the application of the said procedure for useswherein generation of chiral intermediates or products are required in areproducible fashion, as with the preparation of pharmaceutically activeingredient, for instance. Step 1 is the piperazinoimidate formation(i.e., IIe→IIIe) and step 2 is the cyclodehydration step between thesaid imidate and acetylhydrazide (i.e., IIIe+IVe→Ve).

An important disadvantage of the Scheme E procedure is that racemizationof the stereogenic carbon center occurred frequently in steps 2-3.Consequently, the said procedure furnished final products that were onlyinfrequently of acceptable chiral purity; in fact, much more frequently,the Scheme E procedure produced final products represented by thegeneral Formula VIIe, which correspond to compounds of Formula I of thepresent invention, in what is considered essentially racemic by thoseskilled in the art. As such, the said method cannot be used in practiceto prepare a pharmaceutically active ingredient as this method does notreliably furnish chiral intermediates (IIIe, Ve, VIe; Scheme E) and thuscannot be reliably used for obtaining chiral products represented by thegeneral Formula VIIe, which correspond to compounds of Formula I of thepresent invention.

Another disadvantage of the Scheme E procedure is the excessivelyprotracted reaction time required for the cyclodehydration step (SchemeE, IIIe+IVe→Ve). Up to several days (under forcing reactionconditions—see below) were always required with substrates representedby the general Formula IId (Scheme D) wherein R≠H, i.e. the moresterically congested analogs, unlike the case with achiral substratesrepresented by the general Formula IId (Scheme D) wherein R═H. Suchsignificantly protracted reaction times (several days) are not practicalfor such cases as a cGMP scale-up synthesis required to prepare apharmaceutically active ingredient for clinical studies.

As adumbrated in the above paragraph, in the Scheme E procedure, thecyclodehydration step required extremely forcing conditions. Thus, useof elevated temperatures at reflux (for protracted durations), oradditionally with application of essentially maximally feasible (withinmargin of experimental safety) microwave irradiation (sealed vessel)were often required.

Applicant resorted to a racemic synthesis from racemic5,6,7,(8-methyl)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine followed byan additional chiral preparative HPLC purification step after formingthe final product of interest depicted by the general Formula VIIe inScheme E. While feasible on small scale for the initial research anddevelopment phase, such an approach poses the problems of scalability interms of time, cost and general applicability to such needs as cGMPscale-up of a pharmaceutically active ingredients, for instance.

Therefore, there is a need for improving the synthetic procedure forpreparing stereoisomerically pure5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineintermediates for the synthesis of compounds of general Formula I of thepresent invention.

The invention thus also relates to a process of preparing5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineintermediates compounds of Formula II

or salts or solvates thereof, whereinR^(1′) is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl, each ofsaid alkyl or cycloalkyl groups, groups being optionally substituted byone or more group(s) selected from halo or esters; andAr^(2′) is a 5- to 6-membered aryl or heteroaryl group, each of thearyl, or heteroaryl groups being optionally substituted by one or moregroup(s) selected from halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, alkylamino, carbamoyl,alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,alkylsulfonyl, haloalkylsulfonyl, arylsulfonylalkyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, fused to thearyl or heteroaryl group may be one or more cycloalkyl, aryl,heterocyclyl or heteroaryl moiety, each of said substituents beingoptionally substituted by one or more further substituent(s) selectedfrom halo, alkyl, haloalkyl, alkoxy, haloalkoxy;said process comprising the following steps:

-   -   a) reacting a compound of Formula A

whereinR^(1′) is as defined above;with a reagent resulting in a N-sp³ protective group (PG) on the aminenitrogen of compound of Formula A,to obtain a compound of Formula C

b) converting the compound of Formula C with a tri(C1-C2 alkyl) oxoniumsalt so as to obtain a compound of Formula D

wherein R^(1′) and PG are as defined above, and R¹⁰ is C1-C2 alkyl,in the presence of a base;c) reacting the compound of Formula D with a compound of Formula E

or a salt or solvate thereof, whereinAr^(2′) is defined as above with respect to Formula II;so as to obtain a compound of Formula F

wherein R^(1′), PG, and Ar^(2′) are as defined above; andd) deprotecting the compound of Formula F with a suitable deprotectionreagent to afford a compound of Formula II or a salt or solvate thereof.

The process of the invention provides compounds of Formula II or a saltor solvate thereof having good enantiomeric excess of up to 98% andpossibly more in a reproducible fashion.

The process of the invention proceeds with the retention ofstereochemistry with respect to the chiral(3-substituted)-piperazin-2-one starting material except to the extentthat racemization occurs as a minor side-reaction; thus theconfiguration at position 8 of the ring is defined by the configurationof the aforesaid chiral starting material.

According to an advantageous embodiment, through the use of chiral3-substituted-piperazin-2-one starting material, the process of theinvention provides access to5,6,7,((R)-8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinecompounds by minimizing any intervening racemization during the process.

In another aspect, the invention provides compounds of Formula D

wherein R^(1′) is as defined above with respect to Formula II;PG is a protective group wherein the amine nitrogen remains as tertiaryamine (i.e. sp³ hybridized nitrogen), hereafter referred to as N-sp³protective group; andR¹⁰ is C1-C2 alkyl, preferably ethyl.

In still another aspect, the invention provides compounds of Formula III

or salts or solvates thereof, whereinR^(1′) and Ar^(2′) are as defined above with respect to Formula II; andR¹¹ is H or a N-sp³ protective group,with the proviso that the compound of Formula III is not

-   (R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole    hydrochloride,-   (R)-8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   (R)-2-(4-chlorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   (R)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   (S)-8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine,-   (S)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,-   (S)-4-(4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine.

DETAILED DESCRIPTION

Compounds

As noted above, the invention relates to compounds of Formula I, as wellas their pharmaceutically acceptable salts or solvates.

According to one embodiment, the invention provides compounds of generalFormula I′:

and pharmaceutically acceptable solvates thereof, whereinAr¹ is unsubstituted thiophen-2-yl, unsubstituted phenyl, or4-fluorophenyl;R¹ is H or methyl;R² is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear orbranched C2-C3 alkenyl, C3-C4 cycloalkyl or di(C1-C2 alkyl)amino;X¹ is N or C—R⁶ wherein R⁶ is H, fluoro or C1-C2 alkyl;X² is O or S;X³ is N, or X³ is CH under the condition that X¹ is N and X² is N—R⁷wherein R⁷ is linear or branched C1-C3 alkyl or cyclopropyl;with the condition that the compound of Formula I′ is not(3-(2-isobutylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone.

Preferred compounds of Formula I′ and pharmaceutically acceptablesolvates thereof are those wherein

Ar¹ is unsubstituted thiophen-2-yl or unsubstituted phenyl, preferablyAr¹ is unsubstituted thiophen-2-yl; and/or

R¹ is H or methyl, preferably R¹ is methyl; and/or

R² is linear or branched C1-C3 alkyl, C1-C2 haloalkyl, linear orbranched C2-C3 alkenyl, cyclopropyl or di(C1-C2 alkyl)amino, preferablyR² is methyl, ethyl, vinyl, iso-propyl, iso-butyl, C1 fluoroalkyl,cyclopropyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl, trifluoromethyl or cyclopropyl, still more preferably R² ismethyl, ethyl or iso-propyl; even more preferably R² is methyl and/orX¹ is C—R⁶ wherein R⁶ is H or methyl, preferably X¹ is CH; and/orX² is O or S, preferably X² is S; and/orX³ is N.

In one embodiment, preferred compounds of Formula I′ are those ofFormula I′ 1

and pharmaceutically acceptable solvates thereof, wherein Ar¹, R¹, R²,X¹ and X² are as defined above with respect to Formula I′.

Preferred compounds of Formula I′ and pharmaceutically acceptablesolvates thereof are those wherein

Ar¹ is unsubstituted thiophen-2-yl or unsubstituted phenyl, preferablyAr¹ is unsubstituted thiophen-2-yl; and/or

R¹ is H or methyl, preferably R¹ is methyl; and/or

R² is linear or branched C1-C3 alkyl, C1-C2 haloalkyl, linear orbranched C2-C3 alkenyl, cyclopropyl or di(C1-C2 alkyl)amino, preferablyR² is methyl, ethyl, vinyl, iso-propyl, iso-butyl, C1 fluoroalkyl,cyclopropyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl, trifluoromethyl or cyclopropyl; still more preferably R² ismethyl, ethyl or iso-propyl; even more preferably R² is methyl and/orX¹ is C—R⁶ wherein R⁶ is H or methyl, preferably X¹ is CH; and/orX² is O or S, preferably X² is S.

In one embodiment, preferred compounds of Formula I′ 1 are those ofFormulae I′a and I′b:

and pharmaceutically acceptable solvates thereof, whereinAr¹, R², X¹ and X² are as defined above in respect to Formula I′.

Preferred compounds of Formulae I′a and I′b are those wherein

Ar¹ is unsubstituted thiophen-2-yl or unsubstituted phenyl, preferablyAr¹ is unsubstituted thiophen-2-yl; and/or

R² is linear or branched C1-C3 alkyl, C1-C2 haloalkyl, linear orbranched C2-C3 alkenyl, cyclopropyl or di(C1-C2 alkyl)amino, preferablyR² is methyl, ethyl, vinyl, iso-propyl, iso-butyl, C1 fluoroalkyl,cyclopropyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl, trifluoromethyl or cyclopropyl, still more preferably R² ismethyl, ethyl or iso-propyl; even more preferably R² is methyl and/orX¹ is C—R⁶ wherein R⁶ is H or methyl, preferably X¹ is CH; and/orX² is O or S, preferably X² is S.

In one embodiment, preferred compounds of Formula I′ 1 are those ofFormulae I′c and I′d:

and pharmaceutically acceptable solvates thereof, whereinR¹, R², X¹ and X² are as defined above in respect to Formula I′.

Preferred compounds of Formulae I′c and I′d are those wherein

R¹ is H or methyl, preferably R¹ is methyl; and/or

R² is linear or branched C1-C3 alkyl, C1-C2 haloalkyl, linear orbranched C2-C3 alkenyl, cyclopropyl or di(C1-C2 alkyl)amino, preferablyR² is methyl, ethyl, vinyl, iso-propyl, iso-butyl, C1 fluoroalkyl,cyclopropyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl, trifluoromethyl or cyclopropyl, still more preferably R² ismethyl, ethyl or iso-propyl; even more preferably R² is methyl and/orX¹ is C—R⁶ wherein R⁶ is H or methyl, preferably X¹ is CH; and/orX² is O or S, preferably X² is S.

In one embodiment, preferred compounds of Formula I′ 1 are those ofFormulae I′e and I′f:

and pharmaceutically acceptable solvates thereof, whereinAr¹, R¹, R² and R⁶ are as defined above in respect to Formula I′.

Preferred compounds of Formulae I′e and I′f are those wherein

Ar¹ is unsubstituted thiophen-2-yl or unsubstituted phenyl, preferablyAr¹ is unsubstituted thiophen-2-yl; and/or

R¹ is H or methyl, preferably R¹ is methyl; and/or

R² is linear or branched C1-C3 alkyl, C1-C2 haloalkyl, linear orbranched C2-C3 alkenyl, cyclopropyl or di(C1-C2 alkyl)amino, preferablyR² is methyl, ethyl, vinyl, iso-propyl, iso-butyl, C1 fluoroalkyl,cyclopropyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl, trifluoromethyl or cyclopropyl, still more preferably R² ismethyl, ethyl or iso-propyl; even more preferably R² is methyl and/or R⁶is H or methyl, preferably R⁶ is H.

Among the compounds of Formulae I′e and I′f, those of Formula I′f arepreferred.

Other preferred compounds of Formulae I′e and I′f are those of FormulaeI′e-1, I′f-1, I′e-2 and I′f-2

and pharmaceutically acceptable solvates thereof, whereinR¹, R² and R⁶ are as defined above in respect to Formula I′.

Preferred compounds of Formulae I′e-1, I′f-1, I′e-2 and I′f-2 are thosewherein

R¹ is H or methyl, preferably R¹ is methyl; and/or

R² is linear or branched C1-C3 alkyl, C1-C2 haloalkyl, linear orbranched C2-C3 alkenyl, cyclopropyl or di(C1-C2 alkyl)amino, preferablyR² is methyl, ethyl, vinyl, iso-propyl, iso-butyl, C1 fluoroalkyl,cyclopropyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl, trifluoromethyl or cyclopropyl, still more preferably R² ismethyl, ethyl or iso-propyl; even more preferably R² is methyl and/orR⁶ is H or methyl, preferably R⁶ is H.

Among the compounds of Formulae I′e-1, I′f-1, I′e-2 and I′f-2, those ofFormulae I′f-1 and I′f-2 are preferred, those of Formula I′f-2 arefurther preferred.

Preferred compounds of Formula I′e-2 are those of Formula I′e-3

and pharmaceutically acceptable solvates thereof, whereinR² is as defined above in respect to Formula I′e-2, preferably R² ismethyl, ethyl, iso-propyl, iso-butyl, vinyl, cyclopropyl,trifluoromethyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl or cyclopropyl, more preferably R² is methyl, ethyl oriso-propyl, still more preferably R² is ethyl or iso-propyl, even morepreferably R² is iso-propyl.

Preferred compounds of Formula I′f-2 are those of Formula I′f-3

and pharmaceutically acceptable solvates thereof, whereinR² is as defined above in respect to Formula I′e-2, preferably R² ismethyl, ethyl, iso-propyl, iso-butyl, vinyl, cyclopropyl,trifluoromethyl or dimethylamino, more preferably R² is methyl, ethyl,iso-propyl, vinyl, cyclopropyl or dimethylamino more preferably R² ismethyl, ethyl, iso-propyl, vinyl or dimethylamino, still more preferablyR² is methyl or ethyl, even more preferably R² is methyl.

In one embodiment, compounds of Formula I′ are those of Formulae I′g,I′h and I′i

and pharmaceutically acceptable solvates thereof, whereinAr¹, R¹, R² and R⁷ are as defined above in respect to Formula I′.

According to one embodiment, the invention provides compounds of generalFormula I′:

and pharmaceutically acceptable solvates thereof, whereinAr¹ is unsubstituted thiophen-2-yl, unsubstituted phenyl, or4-fluorophenyl;R¹ is H or methyl;R³ is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl;X⁴ is N or C—R⁸ wherein R⁸ is H or C1-C2 alkyl;X⁵ is O or S;X⁶ is N, or X⁶ is CH under the condition that X⁴ is N and X⁵ is N—R⁹wherein R⁹ is linear or branched C1-C3 alkyl or cyclopropyl.

Preferred compounds of Formula I″ and pharmaceutically acceptablesolvates thereof are those wherein

Ar¹ is unsubstituted thiophen-2-yl or unsubstituted phenyl, preferablyAr¹ is unsubstituted thiophen-2-yl; and/or

R¹ is H or methyl, preferably R¹ is methyl; and/or

R³ is methyl or iso-propyl, and/or

X⁴ is N or C—R⁸ wherein R⁸ is H or methyl, X⁵ is O or S and X⁶ is N,preferably X⁴ is N or C—R⁸ wherein R⁸ is H or methyl, X⁵ is S and X⁶ isN; and/or

X⁴ is N, X is N—R⁹ wherein R⁹ is methyl and X⁶ is CH.

In one embodiment, preferred compounds of Formula I″ are those ofFormulae I″a and I″b:

and pharmaceutically acceptable solvates thereof, whereinAr¹, R³, X⁴, X⁵ and X⁶ are as defined above in respect to Formula I″.

Among the compounds of Formulae I″a and I″b, those of Formula I″b arepreferred.

In one embodiment, preferred compounds of Formula I″ are those ofFormulae I″c and I″d:

and pharmaceutically acceptable solvates thereof, whereinR¹, R³, X⁴, X⁵ and X⁶ are as defined above in respect to Formula I″.

Preferred compounds of Formulae I″c and I″d are those wherein

R¹ is H or methyl, preferably R¹ is methyl; and/or

R³ is methyl or iso-propyl; and/or

X⁴ is N or C—R⁸ wherein R⁸ is H or methyl, X⁵ is O or S and X⁶ is N,preferably X⁴ is N or C—R⁸ wherein R⁸ is H or methyl, X⁵ is S and X⁶ isN; and/or

X⁴ is N, X⁵ is N—R⁹ wherein R⁹ is methyl and X⁶ is CH.

In one embodiment, preferred compounds of Formula I″ are those ofFormulae I″e, I″f, I″ g, I″h and I″i:

and pharmaceutically acceptable solvates thereof, whereinAr¹, R¹, R³, R⁸ and R⁹ are as defined above in respect to Formula I″.

Preferred compounds of Formulae I″e, I″f, I″g, I″h and I″i are thosewherein Ar¹ is unsubstituted thiophen-2-yl or unsubstituted phenyl,preferably Ar¹ is unsubstituted thiophen-2-yl; and/or

R¹ is H or methyl, preferably R¹ is methyl; and/or

R³ is methyl or iso-propyl; and/or

R⁸ is H or methyl, preferably H; and/or

R⁹ is methyl.

Among the compounds of Formulae I″e, I″f, I″g, I″h and I″i, those ofFormulae I″e, I″f, I″g and I″h are preferred, in particular those ofFormulae I″f and I″h are further preferred.

Other preferred compounds of Formulae I″e, I″f, I″g, I″h and I″i arethose of Formulae I″e-1, I″f-1, I″g-1, I″h-1, I″i-1, I″e-2, I″f-2,I″g-2, I″h-2 and I″i-2

and pharmaceutically acceptable solvates thereof, whereinR¹, R³, R⁸ and R⁹ are as defined above in respect to Formula I″.

Preferred compounds of Formulae I″e-1, I″f-1, I″g-1, I″h-1, I″i-1,I″e-2, I″f-2, I″g-2, I″h-2 and I″i-2 are those wherein

R¹ is H or methyl, preferably R¹ is methyl; and/or

R³ is methyl or iso-propyl; and/or

R⁸ is H or methyl, preferably H; and/or

R⁹ is methyl.

Among the compounds of Formulae I″e-1, I″f-1, I″g-1, I″h-1, I″i-1,I″e-2, I″f-2, I″g-2, I″h-2 and I″i-2, those of Formulae I″e-1, I″f-1,I″g-1, I″h-1, I″e-2, I″f-2, I″g-2 and I″h-2 are preferred, in particularthose of Formulae I″f-1, I″h-1, I″f-2 and I″h-2 are further preferred.

According to one embodiment, the invention provides compounds of generalFormula I′″:

and pharmaceutically acceptable salts and solvates thereof, whereinAr¹ is unsubstituted phenyl, unsubstituted thiophen-2-yl, or4-fluorophenyl;R⁴ is halo, cyano, methyl, or hydroxyl;R⁵ is H or halo;with the condition that the compound of Formula I′″ is not

-   [1,1′-biphenyl]-4-yl(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;-   (8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone.

Preferred compounds of Formula I″′ and pharmaceutically acceptable saltsand solvates thereof are those wherein

Ar¹ is unsubstituted phenyl, or unsubstituted thiophen-2-yl morepreferably Ar¹ is unsubstituted phenyl; and/or

R⁴ is cyano, methyl or hydroxy, preferably R⁴ is cyano or methyl, morepreferably R⁴ is methyl, and R⁵ is H; and/or

R⁴ is methyl and R⁵ is chloro.

In one embodiment, preferred compounds of Formula I′″ are those ofFormulae I′″a and I′″b:

and pharmaceutically acceptable salts and solvates thereof, whereinR⁴ and R⁵ are as defined above in respect to Formula I″′.

Preferred compounds of Formulae I″′a and I″′b are those wherein

R⁴ is cyano, methyl or hydroxy, preferably R⁴ is cyano or methyl, morepreferably R⁴ is methyl, and R⁵ is H; and/or

R⁴ is methyl and R⁵ is chloro.

Particularly preferred compounds of Formula I of the invention are thoselisted in Table 1 hereafter:

TABLE 1 Cpd n° Structure Chemical name MW 1

(R)-(8-methyl-3-(2- methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 421.53 2

(R)-[1,1′-biphenyl]-4-yl(8- methyl-3-(2-methylthiazol-4-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone415.51 3

(3-(2-methylthiazol-4-yl)- 5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2- yl)phenyl)methanone 407.51 4

(4-(thiophen-2-yl)phenyl)(3- (2-(trifluoromethyl)thiazol-4-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone461.48 5

(R)-(3-(2-ethylthiazol-4-yl)- 8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 435.56 6

(R)-[1,F-biphenyl]-4-yl(3-(2- ethylthiazol-4-yl)-8-methyl- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 429.53 7

(R)-(8-methyl-3-(2- vinylthiazol-4-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone 433.54 8

(R)[1,1′-biphenyl]-4-yl(8- methyl-3-(2-vinylthiazol-4- yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 427.52 9

(4-(thiophen-2-yl)phenyl)(3- (2-vinylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 419.52 10

[1,1′-biphenyl]-4-yl(3-(2- vinylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 413.50 11

(R)-(8-methyl-3-(2- methyloxazol-4-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone 405.47 12

(R)-[1,1′-biphenyl]-4-yl(8- methyl-3-(2-methyloxazol-4- yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 399.44 13

(R)-(3-(2-isopropyloxazol-4- yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 433.52 14

(3-(2-isopropyloxazol-4-yl)- 5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2- yl)phenyl)methanone 419.50 15

(R)-(3-(2-cyclopropyloxazol- 4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 431.51 16

(R)-(3-(2,5-dimethylthiazol- 4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 435.56 17

(R)-(3-(2- (dimethylamino)thiazol-4- yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 450.58 18

(3-(2-isopropylthiazol-4-yl)- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 435.56 19

(R)-(8-methyl-3-(4- methylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 421.54 20

(R)-[1,1′-biphenyl]-4-yl(8- methyl-3-(4-methylthiazol-2-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone415.51 21

[1,1′-biphenyl]-4-yl(3-(4- methylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 401.48 22

(R)-(3-(4,5-dimethylthiazol- 2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 435.57 23

(R)-(8-methyl-3-(3-methyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 406.46 24

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 422.53 25

(R)-(3-(3-isopropyl-1,2,4- thiadiazol-5-yl)-8-methyl- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 450.58 26

(R)-(8-methyl-3-(4- methyloxazol-2-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone 405.47 26

(R)-[1,1′-biphenyl]-4-yl(8- methyl-3-(4-methyloxazol-2- yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 399.45 28

(R)-(3-(1,3-dimethyl-1H- pyrazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 418.51 29

(R)-[1,1′-biphenyl]-4-yl(8- methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone409.48 30

(R-(8-methyl-3-(6- methylpyridin-2-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone 415.51 31

(R)-(3-(6-hydroxypyridin-2- yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 417.48 32

(R)-[1,1′-biphenyl]-4-yl(3-(6- hydroxypyridin-2-yl)-8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone411.45 33

(R)-6-(8-methyl-7-(4- (thiophen-2-yl)benzoyl)- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)picolinonitrile 426.49

In Table 1, the term “Cpd” means compound.

The compounds of Table 1 were named using ChemDraw® Ultra version 12.0(CambridgeSoft, Cambridge, Mass., USA).

The compounds of Formula I can be prepared by different ways withreactions known to a person skilled in the art. Reaction schemes asdescribed in the example section are illustrative only and should not beconstrued as limiting the invention in any way. According to oneembodiment, compounds of Formula I can be prepared using the chiralsynthesis of the invention detailed below.

The invention is further directed to the use of the compounds of theinvention or pharmaceutically acceptable salts or solvates thereof asantagonists to the NK-3 receptor.

Accordingly, in a particularly preferred embodiment, the inventionrelates to the use of compounds of Formula I and subformulae inparticular those of table 1 above, or pharmaceutically acceptable saltsor solvates thereof, as NK-3 receptor antagonists.

Chiral Synthesis

As noted above, the invention relates to a novel process for thepreparation of compounds of Formula II which comprises the abovedescribed steps a) to d).

In one embodiment, the process of the invention is directed to thepreparation of5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinecompounds of Formula II as defined above or salts or solvates thereof,wherein R^(1′) and Ar^(2′) are as defined above; and steps a) to d) areas follows:

a) reacting a compound of Formula A

wherein R^(1′) is as defined above;with a reagent resulting in an N-sp³ protective group on the aminenitrogen of compound of Formula A of Formula B1 or Formula B2

wherein,R¹², R^(12′), R¹³, R^(13″) and R¹⁴ are H, or R¹⁴ is methoxy and R¹²,R^(12′) R¹³ and R^(13′) are H, or R¹² and R¹⁴ are methoxy and R^(12′),R¹³ and R^(13′) are H, or R¹², R^(12′) and R¹⁴ are methoxy and R¹³ andR^(13′) are H,X is Cl, Br, I, OMs, OTs, OTf,either through direct alkylation of the amine nitrogen when compound ofFormula B2 is used, or in the presence of a reducing agent when acompound of Formula B1 is used to ultimately obtain a compound ofFormula C-1

wherein R^(1′), R¹², R^(12′), R¹³, R^(13′) and R¹⁴ are as defined above;b) converting the compound of Formula C-1 with a tri(C1-C2 alkyl)oxoniumsalt (Meerwein-type reagents), or (C1-C2)alkylsulfate, or(C1-C2)chloroformate, or use of PCl₅/POCl₃/(C1-C2)hydroxyalkyl so as toobtain a compound of Formula D-1

wherein R^(1′), R¹², R^(12′), R¹³, R^(13′) and R¹⁴ are as defined aboveand R¹⁰ is C1-C2 alkyl, in the presence of a base;c) reacting the compound of Formula D-1 with a compound of Formula E

or a salt or solvate thereof, whereinAr^(2′) is defined as above with respect to Formula II;so as to obtain a compound of Formula F-1

wherein R^(1′), R¹², R^(12′), R¹³, R^(13′), R¹⁴ and Ar^(2′) are asdefined above; andd) deprotecting the compound of Formula F-1 with a suitable deprotectionreagent as defined herein to afford a compound of Formula II or an saltor solvate thereof.

Preferred compounds of Formula Hand salts or solvates thereof are thosewherein

R^(1′) is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl, each ofsaid alkyl or cycloalkyl groups, groups being optionally substituted byone ester group; preferably R^(1′) is linear or branched C1-C4 alkyl orC3-C4 cycloalkyl; or

R^(1′) is C1-C2 alkyl, optionally substituted by one ester group;preferably R^(1′) is methyl optionally substituted by one ester group,more preferably R^(1′) is methyl; and/or

Ar^(2′) is a 5- to 6-membered aryl or heteroaryl group, each of thearyl, or heteroaryl groups being optionally substituted by one or moregroup(s) selected from halo, alkyl, haloalkyl, cycloalkyl, aryl,heteroaryl, hydroxyl, alkoxy, alkylamino, carbamoyl, alkylcarbamoyl,carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, or fused to thearyl or heteroaryl group may be one or more cycloalkyl, aryl,heterocyclyl or heteroaryl moiety, each of said substituents beingoptionally substituted by one or more further substituent(s) selectedfrom halo, alkyl, haloalkyl, alkoxy, haloalkoxy; preferably Ar^(2′) is a5- to 6-membered aryl or heteroaryl group, each of the aryl, orheteroaryl groups being optionally substituted by one or more group(s)selected from halo, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl,hydroxyl, alkoxy, alkylamino, carbamoyl, alkylcarbamoyl, carbamoylalkyl,carbamoylamino, alkylcarbamoylamino; more preferably Ar^(2′) is a 5- to6-membered aryl or heteroaryl group, each of the aryl, or heteroarylgroups being optionally substituted by one or more group(s) selectedfrom halo, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxyl,alkylamino; still more preferably Ar^(2′) is a 5- to 6-membered aryl orheteroaryl group, each of the aryl, or heteroaryl groups beingoptionally substituted by one or more group(s) selected from fluoro,branched or linear C1-C4 alkyl, C3-C4 cycloalkyl halo(C1)alkyl,cyclopropyl, aryl, hydroxyl, alkylamino; and most preferably Ar^(2′) isa 5- to 6-membered heteroaryl group selected from the group consistingof rings (i), (ii) and (iii)

-   -   wherein    -   X¹ is N or C—R⁶ wherein R⁶ is H, fluoro or methyl; preferably X¹        is C—R⁶ wherein R⁶ is H or methyl, more preferably X¹ is CH;        and/or    -   X² is O or S; preferably X² is S; and/or    -   X³ is N, or X³ is CH under the condition that X¹ is N and X² is        N—R⁷ wherein R⁷ is linear or branched C1-C3 alkyl or        cyclopropyl; preferably X³ is N; and/or    -   R^(2′) is linear or branched C1-C4 alkyl, C1-C2 haloalkyl,        linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl, di(C1-C2        alkyl)amino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl or        N-morpholinyl; preferably R^(2′) is methyl, ethyl, iso-propyl,        C1 fluoroalkyl, cyclopropyl, dimethylamino, phenyl,        4-fluorophenyl, 2,4-difluorophenyl or or N-morpholinyl; more        preferably R^(2′) is methyl, ethyl, iso-propyl, trifluoromethyl        or cyclopropyl, still more preferably R^(2′) is methyl, ethyl or        iso-propyl; most preferably R^(2′) is methyl; and/or    -   X⁴ is N or C—R⁸ wherein R⁸ is H or C1-C2 alkyl, X⁵ is O or S, X⁶        is N or X⁶ is CH under the condition that X⁴ is N and X⁵ is N—R⁹        wherein R⁹ is C1-C2 alkyl or C3 cycloalkyl, or X⁴ is N, X⁵ is        N—R⁹ wherein R⁹ is methyl and X⁶ is CH; preferably X⁴ is N or        C—R⁸ wherein R⁸ is H or methyl, X⁵ is O or S and X⁶ is N; more        preferably X⁴ is N or C—R⁸ wherein R⁸ is H or methyl, X⁵ is S        and X⁶ is N; and/or    -   R^(3′) is linear or branched C1-C4 alkyl, C1-C2 haloalkyl,        linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl, di(C1-C2        alkyl)amino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl or        N-morpholinyl; more preferably R^(3′) is linear or branched        C1-C4 alkyl or C3 cycloalkyl; even more preferably R^(3′) is        methyl or iso-propyl; and/or    -   R^(4′) is cyano, C1-C2 alkyl or hydroxyl, preferably R^(4′) is        cyano, methyl or hydroxyl, preferably R^(4′) is methyl or        hydroxyl, still more preferably R^(4′) is methyl.

Particularly preferred compounds of Formula II are those listed in table2 hereafter:

TABLE 2 Cpd n° Structure Chemical name MW  1

(R)-2-methyl-4-(8-methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31  2

(S)-2-methyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31  3

(R)-2-ethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34  4

(S)-2-ethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34  5

(R)-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole 247.32  6

(S)-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole 247.32  7

(R)-2-methyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24  8

(S)-2-methyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24  9

(R)-2-isopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 247.30 10

(S)-2-isopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 247.30 11

(R)-2-cyclopropyl-4-(8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 245.28 12

(S)-2-cyclopropyl-4-(8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 245.28 13

(R)-2,5-dimethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 14

(S)-2,5-dimethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 15

(R)-N,N-dimethyl-4-(8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazol-2-amine 264.35 16

(S)-N,N-dimethyl-4-(8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazol-2-amine 264.35 17

(R)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31 18

(S)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31 19

(R)-4,5-dimethyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 20

(S)-4,5-dimethyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 21

(R)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-oxadiazole 220.23 22

(S)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-oxadiazole 220.23 23

(R)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 236.30 24

(S)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 236.30 25

(R)-3-isopropyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 264.35 26

(S)-3-isopropyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 264.35 27

(R)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24 28

(S)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24 29

(R)-3-(1,3-dimethyl-1H- pyrazol-5-yl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 232.29 30

(S)-3-(1,3-dimethyl-1H- pyrazol-5-yl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 232.29 31

(R)-8-methyl-3-(6- methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 229.28 32

(S)-8-methyl-3-(6- methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 229.28 33

(R)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol 231.25 34

(S)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol 231.25 35

(R)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)picolinonitrile 240.26 36

(S)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)picolinonitrile 240.26

The compounds of Table 2 were named using ChemDraw Ultra 12® purchasedfrom CambridgeSoft (Cambridge, Mass., USA).

The below description of the process of the invention applies to theprocess of the invention as defined above, including all embodimentsdescribed.

Step a) of the process as defined above is the preparation of compoundsof Formula C through reaction of the amine group of a compound ofFormula A with a reagent resulting in a N-sp³ protective group, asdefined herein, on the amine nitrogen of compound of Formula A usingstandard reductive amination conditions.

The compound of Formula A is advantageously selected from those whereinR^(1′) is a C1-C4 alkyl, each of said alkyl groups being optionallysubstituted by one or more group(s) selected from halo or esters,preferably R^(1′) is methyl.

This reaction results in the protection of the amine nitrogen of thepiperazinone of Formula A with an above-defined N-sp³ protective group(compound of Formula C), in particular with a benzylic protective groupwhen a compound of Formula B1 or B2 is used (compound of Formula C-1).

The reagent resulting in a N-sp³ protective group, as defined herein, onthe amine nitrogen of compound of Formula A is advantageously a compoundof Formula B1 or B2 as defined above. The compound of Formula B1 or B2is advantageously selected from those wherein R¹⁴ is methoxy and R¹²,R^(12′), R¹³ and R^(13′) are H, or R¹² and R¹⁴ are methoxy and R^(12′),R¹³ and R^(13′) are H, or R¹², R^(12′) and R¹⁴ are methoxy and R¹³ andR^(13′) are H, in particular the compound of Formula B is the onewherein R¹² and R¹⁴ are methoxy and R^(12′), R¹³ and R^(13′) are H;and/or

The term “benzylic protective groups” according to the invention isdefined as benzyl (Bn), 4-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB)and 2,4,6-trimethoxybenzyl (TMB), among which DMB and TMB, in particularDMB, are preferred.

These benzylic protective groups proved advantageous since their useresulted in significant reduction of racemization during the steps b),c) and d) as compared to when other protective groups such as Boc(tert-butyloxycarbonyl) and Cbz (carbobenzyloxy) were used to conductsteps b), c) and d).

Without being exclusively bound by any theory, Applicant considers twoconjectures as potentially relevant to the significant improvements inthe improved chiral synthesis procedure disclosed in this invention.Firstly, that N-sp³ protective groups, as defined herein, e.g. Bn, PMB,DMB, TMB, in contrast to the “N-sp² protective groups”, i.e. carbamatessuch as Boc, Cbz, Alloc (allyloxycarbonyl), may be considered lesselectron-withdrawing, thus rendering the hydrogen at the stereogeniccarbon center less labile and, consequently, less prone to racemization.Secondly, the greater reaction efficiency in terms of reaction time andgenerally milder reaction conditions (e.g. obviating the need for largeexcess of Meerwein reagent) observed in both the imidate formation (stepb) and cyclodehydration steps (step c) with N-sp³ protective groups suchas Bn, PMB, DMB likely contributes to retaining the chiral purity thatoriginates from the starting material, e.g. a chiral form of3-methylpiperazin-2-one, and, consequently furnishing the intermediatesthereof and the final products of this invention in high enantiomericpurity as defined herein.

As already set forth above, step a) is carried out in the presence of areducing agent. The term “reducing agent” as used herein means allreagents that can reduce an imine to an amine, such as suitablehydrogenolytic conditions, including but not limited to using NaBH₄ andrelated derivatives, tri(C1-C2alkyl)silanes, boranes, andhydride-transfer reagents.

The reducing agent is advantageously an alkaline cation borohydridereagent, which is preferably selected from the group consisting ofsodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride, sodium trifluroracetoxyborohydride, morepreferably the reducing agent is sodium triacetoxyborohydride.

Step a) is carried out according to standard procedures well known tothose skilled in the art (See for example (a) Wuts, P. G. M.; Greene, T.W. In “Greene's Protective Groups in Organic Synthesis”,Wiley-Interscience: New York, 4^(th) Edition, Chap. 7, pp. 696-926, and(b) Kocieński, P. J. In “Protecting Groups”, Georg Thieme Verlag:Stuttgart, N.Y.; 3^(rd) Edition, Chap. 8, pp. 487-643).

Intermediates of Formula A may be optionally purified by silica gelflash chromatography or silica gel chromatography, and/or precipitation,and/or trituration, and/or filtration, and/or recrystallization.

The second step of the process, step b), is the conversion of theketopiperazine compounds of Formula C to iminoether compounds of FormulaD, in particular of ketopiperazine compounds of Formula C-1 toiminoether compounds of Formula D-1.

Unlike the case with the N-sp² protective groups, such as Boc, withN-sp³ protective groups, step b) proceeds without significant loss ofchirality resulting in the corresponding products of good enantiomericpurity as defined herein.

The procedure involves a tri(C1-C2 alkyl)oxonium salt (Meerwein-typereagents), or (C1-C2)alkylsulfate, or (C1-C2)chloroformate, or use ofPCl₅/POCl₃/(C1-C2)hydroxyalkyl, preferably tri(C1-C2 alkyl)oxonium salt(Meerwein-type reagents), or (C1-C2)alkylsulfate, more preferablytri(C1-C2 alkyl)oxonium salt, and even more preferably a tri(C2alkyl)oxonium salt, such as Et₃OBF₄.

As set out above, step b) is carried out in the presence of a base.

Use of at least 2 equivalents of tri(C1-C2 alkyl)oxonium salt (1) withrespect to the 3-substituted-piperazin-2-one was required to aid towardsa complete conversion when step b) was carried out without a mild baseadditive, such as Na₂CO₃, as further discussed hereunder.

Without being bound by any theory, Applicant believes that formation ofan acid such as HBF₄ that may be a side-product with the use ofmoisture-sensitive tri(C1-C2 alkyl)oxonium salt (Meerwein-type reagents)may additionally contribute to the variability in the product qualityaforementioned. Interestingly, there exist two literature references(See (a) Sánchez, J. D. et al. J. Org. Chem. 2001, 66, 5731-5735; (b)Kende, A. S.; et al. Org. Lett. 2003, 5, 3205-3208) that cite the use ofmild bases such as Na₂CO₃ in conjunction with the use of Meerweinreagent although without offering any explicit rationale or detailedexperimental conditions. After extensive reaction optimizationexperiments, Applicant found that addition of a base, especially Na₂CO₃,with respect to the Meerwein reagent helped minimize racemization.Applicant further observed that use of a mild base additive, especiallyNa₂CO₃, appears to also help accelerate the reaction towards completionthat in turn may contribute to minimizing racemization in suchreactions.

The base is advantageously selected from the group consisting of sodiumcarbonate, sodium bicarbonate, potassium carbonate, cesium carbonate,preferably the base is sodium carbonate.

In a preferred embodiment, between 1 and 5, preferably about 1.8 moleequivalents with respect to tri(C1-C2 alkyl)oxonium salt of base areused.

The tri(C1-C2 alkyl)oxonium salt is advantageously selected from thegroup consisting of trimethyloxonium tetrafluoroborate, triethyloxoniumtetrafluoroborate, preferably the tri(C1-C2 alkyl) oxonium salt istriethyloxonium tetrafluoroborate. In an advantageous embodiment,between 1 and 2, preferably about 1.4, mole equivalents of tri(C1-C2alkyl)oxonium salt is used.

The iminoether synthesis step b) is advantageously carried out in anorganic, preferably anhydrous, solvent, preferably dichloromethane.

The reaction is advantageously carried out at a temperature equal to orbelow the boiling point of the organic solvent; preferably the reactionis carried out at room temperature.

The term “room temperature” as used herein means a temperature comprisedbetween 10° C. and 30° C., preferably about 20±5° C.

In one embodiment, especially in the case of the conversion ofketopiperazine compounds of Formula C-1 to iminoether compounds ofFormula D-1, step b) is carried out in DCM, at room temperature with 1.8equivalents with respect to tri(C1-C2 alkyl)oxonium salt of sodiumcarbonate.

Intermediates of Formula D may optionally be purified by flash or columnchromatography on silica gel.

The third step of the process, step c), is the preparation oftriazolopiperazine compounds of Formula F by condensation between animinoether of Formula D and an acylhydrazide of Formula E or a salt orsolvate thereof, especially the preparation of triazolopiperazinecompounds of Formula F-1 by condensation between an iminoether ofFormula D-1 and an acylhydrazide of Formula E or salt or solvatethereof.

Without being bound by any theory, Applicant believes that when usingN-sp² protective groups, such as Boc, the inductive effect of thecarbamate makes the proton at the C8 position more acidic, which couldthus explain the observed racemization (deprotonation might occur in thepresence of hydrazide).

Step c) is generally carried out at a temperature comprised between 50°C. and 135° C., preferably between 70° C. and 135° C.

In contrast, condensations with Boc-protected methylketopiperazine weretypically conducted under very forcing conditions, such as 135° C., neatreaction medium, long reaction time (>24 h) or excessive application ofmicrowave for several days. Such conditions were not readily amenablefor scale-up, and in addition, non-reproducible chiral purity was also aproblem with such harsh and protracted reaction conditions.

Intermediates of Formula F may optionally be purified by flash or columnchromatography on silica gel.

The fourth step of the process, i.e. step d), entails deprotection ofcompounds of Formula F especially compounds of Formula F-1 with asuitable deprotection reagent.

The term “suitable deprotection reagent” according to the invention isdefined as any reagent(s) allowing the removal of an N-sp³ protectivegroup as defined herein, in particular benzylic protective groups asdefined herein. Examples of such reagents are reported in (a) Wuts, P.G. M.; Greene, T. W. In “Greene's Protective Groups in OrganicSynthesis”, Wiley-Interscience: New York, 4^(th) Edition, Chap. 7, pp.696-926, and (b) Kocieński, P. J. In “Protecting Groups”, Georg ThiemeVerlag: Stuttgart, N.Y.; 3^(rd) Edition, Chap. 8, pp. 487-643); suitabledeprotection reagents include but are not limited to hydrogenolyticconditions (e.g. H₂, Pd/C) or acidolytic conditions (e.g. HCl, TFA).

Preferred deprotection reagents are selected from the group consistingof TFA, HCl, preferably HCl.

The more acid labile variants of the benzylic protective groups asdefined herein, such as PMB, DMB and TMB, proved advantageous due tomilder deprotection conditions required, thus consequently aiding inminimizing any racemization possible at this step.

Step d) is advantageously carried out in an organic solvent selectedfrom 1,4-dioxane, dichloromethane, iso-propanol.

When using acidolytic deprotection conditions such as through the use ofTFA or HCl, compounds of Formula II are thus obtained in theircorresponding salt forms.

In one embodiment, step d) may be optionally followed by a conversion tothe free base form.

In one embodiment, compounds of Formula II, either in salt or free baseform, are converted using stereoisomeric salt-forming agents, such aschiral acids, to obtain stereoisomeric salts of Formula II in order toenhance the chemical purity and/or stereoisomeric purity of the finalintermediate.

The aforesaid stereoisomeric salt-forming agents include but are notlimited to mandelic acid, tartaric acid, dibenzoyl- andditoluyl-tartaric acid, phenylpropionic acid, tartanilic acidderivatives in all relevant stereoisomeric forms, or more preferablymandelic acid, tartaric acid, dibenzoyl- and ditoluyl-tartaric acid,phenylpropionic acid in all relevant stereoisomeric forms.

In one embodiment, step d) is followed by an additional amide couplingstep e) in which the compound of Formula II or salt or solvate thereofis reacted with a compound of Formula G

or a salt or solvate thereof, whereinAr¹ is phenyl, thiophen-2yl or 4-fluorophenyl, preferably phenyl orthiophen-2-yl;Y is hydroxyl, halo, preferably F or Cl, more preferably hydroxyl andCl, and even more preferably Cl;to provide a compound of Formula H

or a salt or solvate thereof wherein Ar^(2′) is as defined above withrespect to Formula II and Ar¹ is as defined above with respect toFormula G.

Step e) is advantageously carried out in an organic, preferablyanhydrous, solvent, selected from dichloromethane, acetonitrile,preferably in dichloromethane.

The reaction is advantageously carried out at a temperature equal to orbelow boiling point of the organic solvent, preferably at roomtemperature.

In the case of compounds of Formula G wherein Y is a halo, the reactionis carried out in the presence of a base selected from the groupconsisting of di-iso-propylethylamine, N-methylmorpholine,triethylamine, preferably N-methylmorpholine, and in the case ofcompounds of Formula G wherein Y is a hydroxyl, an activated anhydride,ester, acylurea derivative of the latter said compounds—formed throughconventional amide bond forming reagent(s) involving the use ofso-called activating groups, such as isobutylchloroformate, DIC, DCC,HOBt, HATU, HBTU, DEPBT under reaction conditions known to those skilledin the art, and more preferably with compounds of Formula G wherein Y isa halo, the reaction was carried out in the presence of a base selectedfrom the group consisting of di-iso-propylethylamine,N-methylmorpholine, triethylamine, preferably N-methylmorpholine;

Enantiomeric excess values of compounds of Formula II or salt thereofwere not determined since separation on chiral HPLC was difficult toachieve. However, chiral purity and enantiomeric excess of compounds ofFormula G could be determined. Applicant has observed identical eevalues for compounds of Formula D and amides of Formula H whichconfirmed both steps d) and e) proceed without any detectableracemisation (chiral LC).

In another aspect, the invention provides intermediates for thesynthesis of compounds of Formula II, in particular according to theprocess of the invention. These intermediates are compounds of Formula Das defined above.

In one embodiment, compounds of Formula D are those of formula D-1

whereinR^(1′) and R¹⁰ are as defined with respect to Formula D; andR¹², R^(12′), R¹³, R^(13′) and R¹⁴ are H, or R¹⁴ is methoxy and R¹²,R^(12′), R¹³ and R^(13′) are H, or R¹² and R¹⁴ are methoxy and R^(12′),R¹³ and R^(13′) are H, or R¹², R^(12′) and R¹⁴ are methoxy and R¹³ andR^(13′) are H.

Preferred compounds of Formula D-1 are those wherein:

R¹⁴ is methoxy and R¹², R^(12′), R¹³ and R^(13′) are H, or R¹² and R¹⁴are methoxy and R^(12′), R¹³ and R^(13′) are H, or R¹², R^(12′) and R¹⁴are methoxy and R¹³ and R^(13′) are H, preferably R¹² and R¹⁴ aremethoxy and R^(12′), R¹³ and R^(13′) are H, or R¹², R^(12′) and R¹⁴ aremethoxy and R¹³ and R^(13′) are H, more preferably R¹² and R¹⁴ aremethoxy and R^(12′), R¹³ and R^(13′) are H; and/orR¹⁰ is ethyl.

A preferred compound of Formula D-1 is(R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine.

As set forth above, the invention also provides compounds of Formula IIIas defined above. In one embodiment, compounds of Formula III or saltsor solvates thereof are those wherein

R¹¹ is H or

whereinR¹², R^(12′), R¹³, R^(13′) and R¹⁴ are H, or R¹⁴ is methoxy and R¹²,R^(12′), R¹³ and R¹³ are H, or R¹² and R¹⁴ are methoxy and R^(12′), R¹³and R^(13′) are H, or R¹², R^(12′) and R¹⁴ are methoxy and R¹³ andR^(13′) are H; preferably R¹⁴ is methoxy and R¹², R^(12′), R¹³ and R¹³are H, or R¹² and R¹⁴ are methoxy and R^(12′), R¹³ and R^(13′) are H, orR¹², R^(12′) and R¹⁴ are methoxy and R¹³ and R^(13′) are H, preferablyR¹² and R¹⁴ are methoxy and R^(12′), R¹³ and R¹³ are H, or R¹², R^(12′)and R¹⁴ are methoxy and R¹³ and R^(13′) are H, more preferably R¹² andR¹⁴ are methoxy and R^(12′), R¹³ and R^(13′) are H; andR^(1′) and Ar^(2′) is as defined with respect to Formula II.

Particularly preferred compounds of Formula III are those listed intable 3 hereafter:

TABLE 3 Cpd n° Structure Chemical name MW  1

(R)-2-methyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31  2

(S)-2-methyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31  3

(R)-2-ethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34  4

(S)-2-ethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34  5

(R)-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-vinylthiazole 247.32  6

(S)-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-vinylthiazole 247.32  7

(R)-2-methyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24  8

(S)-2-methyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24  9

(R)-2-isopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 247.30 10

(S)-2-isopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 247.30 11

(R)-2-cyclopropyl-4-(8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 245.28 12

(S)-2-cyclopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 245.28 13

(R)-2,5-dimethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 14

(S)-2,5-dimethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 15

(R)-N,N-dimethyl-4-(8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazol-2-amine 264.35 16

(S)-N,N-dimethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazol-2-amine 264.35 17

(R)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31 18

(S)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 235.31 19

(R)-4,5-dimethyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 20

(S)-4,5-dimethyl-2-(8-methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)thiazole 249.34 21

(R)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-oxadiazole 220.23 22

(S)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-oxadiazole 220.23 23

(R)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 236.30 24

(S)-3-methyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 236.30 25

(R)-3-isopropyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 264.35 26

(S)-3-isopropyl-5-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-1,2,4-thiadiazole 264.35 27

(R)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24 28

(S)-4-methyl-2-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 219.24 29

(R)-3-(1,3-dimethyl-1H- pyrazol-5-yl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 232.29 30

(S)-3-(1,3-dimethyl-1H- pyrazol-5-yl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 232.39 31

(R)-8-methyl-3-(6- methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 229.28 32

(S)-8-methyl-3-(6- methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 229.28 33

(R)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol 231.25 34

(S)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol 231.25 35

(R)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)picolinonitrile 240.26 36

(S)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3a]pyrazin-3-yl)picolinonitrile 240.26 37

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-methylthiazole 385.48 38

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-methylthiazole 385.48 39

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-ethylthiazole 399.51 40

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-ethylthiazole 399.51 41

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-vinylthiazole 397.49 42

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-vinylthiazole 397.49 43

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-methyloxazole 369.42 44

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-methyloxazole 369.42 45

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-isopropyloxazole 397.47 46

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-isopropyloxazole 397.47 47

(R)-2-cyclopropyl-4-(7-(2,4- dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 395.4648

(S)-2-cyclopropyl-4-(7-(2,4- dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin- 3-yl)oxazole 395.4649

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2,5-dimethylthiazole 399.51 50

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2,5-dimethylthiazole 399.51 51

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-N,N-dimethylthiazol-2- amine 414.5252

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-N,N-dimethylthiazol-2- amine 414.5253

(R)-2-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-4-methylthiazole 385.48 54

(S)-2-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-4-methylthiazole 385.48 55

(R)-2-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-4,5-dimethylthiazole 399.51 56

(S)-2-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-4,5-dimethylthiazole 399.51 57

(R)-5-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin 3-yl)-3-methyl-1,2,4- oxadiazole 370.41 58

(S)-5-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin 3-yl)-3-methyl-1,2,4- oxadiazole 370.41 59

(R)-5-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-3-methyl-1,2,4- thiadiazole 386.4760

(S)-5-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-3-methyl-1,2,4- thiadiazole 386.4761

(R)-5-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-3-isopropyl-1,2,4- thiadiazole414.52 62

(S)-5-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-3-isopropyl-1,2,4- thiadiazole414.52 63

(R)-2-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-4-methyloxazole 369.42 64

(S)-2-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-4-methyloxazole 369.42 65

(R)-7-(2,4-dimethoxybenzyl)- 3-(1,3-dimethyl-1H-pyrazol-5-yl)-8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 382.4666

(S)-7-(2,4-dimethoxybenzyl)- 3-(1,3-dimethyl-1H-pyrazol-5-yl)-8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 382.4667

(R)-7-(2,4-dimethoxybenzyl)- 8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine 379.46 68

(S)-7-(2,4-dimethoxybenzyl)- 8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine 379.46 69

(R)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol compound with 1-ethyl-2,4- dimethoxybenzene(1:1) 397.47 70

(S)-6-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol compound with 1-ethyl-2,4- dimethoxybenzene(1:1) 397.47 71

(R)-6-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)picolinonitrile 390.44 72

(S)-6-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)picolinonitrile 390.44 73

(R)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-(4- fluorophenyl)thiazole 465.5474

(S)-4-(7-(2,4- dimethoxybenzyl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin- 3-yl)-2-(4- fluorophenyl)thiazole 465.54

Compounds of Formula D, especially D-1, and Formula III, in particular(R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazineand those of table 3 above, or salts or solvates thereof areparticularly interesting for the synthesis of chiral5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines, whichare useful intermediates for the synthesis of pharmaceutical activeingredients, such as selective NK-3 receptor antagonists.

Accordingly, in another aspect, the invention relates to the use ofthese compounds or salts or solvates thereof for the synthesis ofpharmaceutical active ingredients, such as selective NK-3 receptorantagonists.

Applications

The compounds of the invention are therefore useful as medicaments, inparticular in the prevention and/or treatment of depression, anxiety,pyschosis, schizophrenia, psychotic disorders, bipolar disorders,cognitive disorders, Parkinson's disease, Alzheimer's disease, attentiondeficit hyperactivity disorder (ADHD), pain, convulsion, obesity,inflammatory diseases including irritable bowel syndrome andinflammatory bowel disorders, emesis, pre-eclampsia, airway relateddiseases including chronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, reproductiondisorders, contraception and sex hormone-dependent diseases includingbut not limited to benign prostatic hyperplasia (BPH), prostatichyperplasia, metastatic prostatic carninoma, testicular cancer, breastcancer, ovarian cancer, androgen dependent acne, male pattern baldness,endometriosis, abnormal puberty, uterine fibrosis, uterine fibroidtumor, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoricdisease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistanceand acanthosis nigricans), ovarian hyperthecosis (HAIR-AN withhyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis.

The invention also provides for a method for delaying in patient theonset of depression, anxiety, pyschosis, schizophrenia, psychoticdisorders, bipolar disorders, cognitive disorders, Parkinson's disease,Alzheimer's disease, attention deficit hyperactivity disorder (ADHD),pain, convulsion, obesity, inflammatory diseases including irritablebowel syndrome and inflammatory bowel disorders, emesis, pre-eclampsia,airway related diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders, contraception and sex hormone-dependent diseasesincluding but not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carninoma, testicularcancer, breast cancer, ovarian cancer, androgen dependent acne, malepattern baldness, endometriosis, abnormal puberty, uterine fibrosis,uterine fibroid tumor, hormone-dependent cancers, hyperandrogenism,hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrualdysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulinresistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-ANwith hyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosiscomprising the administration of a pharmaceutically effective amount ofa compound of Formula I or pharmaceutically acceptable salts or solvatethereof to a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

The compounds of the invention are also useful in the treatment ofgynecological disorders and infertility. In particular, the inventionprovides methods to suppress the LH-surge in assisted conception.

The compounds of the invention are also useful to cause male castrationand to inhibit the sex drive in men. This is of particular interest inthe treatment of male sexual offenders.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable salts or solvate thereof for the manufactureof a medicament for treating and/or preventing depression, anxiety,pyschosis, schizophrenia, psychotic disorders, bipolar disorders,cognitive disorders, Parkinson's disease, Alzheimer's disease, attentiondeficit hyperactivity disorder (ADHD), pain, convulsion, obesity,inflammatory diseases including irritable bowel syndrome andinflammatory bowel disorders, emesis, pre-eclampsia, airway relateddiseases including chronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, reproductiondisorders, contraception and sex hormone-dependent diseases includingbut not limited to benign prostatic hyperplasia (BPH), prostatichyperplasia, metastatic prostatic carninoma, testicular cancer, breastcancer, ovarian cancer, androgen dependent acne, male pattern baldness,endometriosis, abnormal puberty, uterine fibrosis, uterine fibroidtumor, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoricdisease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistanceand acanthosis nigricans), ovarian hyperthecosis (HAIR-AN withhyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis in apatient.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable salts or solvate thereof for the manufactureof a medicament to suppress the LH-surge in assisted conception in apatient. Preferably the patient is a warm-blooded animal, morepreferably a woman.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable salts or solvate thereof for the manufactureof a medicament to cause male castration and to inhibit the sex drive inmen. This is of particular interest in the treatment of male sexualoffenders.

According to a further feature of the present invention there isprovided a method for modulating NK-3 receptor activity, in a patient,preferably a warm blooded animal, and even more preferably a human, inneed of such treatment, which comprises administering to said patient aneffective amount of compound of the present invention, or apharmaceutically acceptable salts or solvate thereof.

According to one embodiment, the compounds of the invention, theirpharmaceutical acceptable salts or solvates may be administered as partof a combination therapy. Thus, are included within the scope of thepresent invention embodiments comprising coadministration of, andcompositions and medicaments which contain, in addition to a compound ofthe present invention, a pharmaceutically acceptable salts or solvatethereof as active ingredient, additional therapeutic agents and/oractive ingredients. Such multiple drug regimens, often referred to as“combination therapy”, may be used in the treatment and/or prevention ofany of the diseases or conditions mediated by or associated with NK-3receptor modulation. The use of such combinations of therapeutic agentsis especially pertinent with respect to the treatment of theabove-mentioned disorders within a patient in need of treatment or oneat risk of becoming such a patient.

In addition to the requirement of therapeutic efficacy, which maynecessitate the use of active agents in addition to the NK-3 receptormodulator compounds of Formula I or pharmaceutical salts or acceptablesolvates thereof, there may be additional rationales which compel orhighly recommend the use of combinations of drugs involving activeingredients which represent adjunct therapy, i.e., which complement andsupplement the function performed by the NK-3 receptor modulatorcompounds of the present invention. Suitable supplementary therapeuticagents used for the purpose of auxiliary treatment include drugs which,instead of directly treating or preventing a disease or conditionmediated by or associated with NK-3 receptor modulation, treat diseasesor conditions which directly result from or indirectly accompany thebasic or underlying NK-3 receptor modulated disease or condition.

According to a further feature of the present invention, the compound ofFormula I, a pharmaceutically acceptable salts or solvate thereof may beused in combination therapy with antipsychotic drugs (APD), to improvethe efficacy and to minimize secondary effects associated to APDincluding but not limited to Dopamine 2/3 and 5-HT2 receptorsantagonists. More particular the compound of Formula I, apharmaceutically acceptable salts or solvate thereof may be used as anadjunct therapy in combination with an atypical antipsychotic drug,including but not limited to risperidone, clozapine, olanzapine, wherethe NK-3 receptor modulator may serve a role as dose-limiting for theatypical antipsychotic and therefore spare the patient from some of theside effect of those atypical antipsychotic drugs.

Thus, the methods of treatment and pharmaceutical compositions of thepresent invention may employ the compounds of Formula I orpharmaceutical acceptable solvates thereof in the form of monotherapy,but said methods and compositions may also be used in the form ofmultiple therapy in which one or more compounds of Formula I or theirpharmaceutically acceptable salts or solvates are coadministered incombination with one or more other therapeutic agents.

In the above-described embodiment combinations of the present invention,the compound of Formula I, a pharmaceutically acceptable salts orsolvate thereof and other therapeutic active agents may be administeredin terms of dosage forms either separately or in conjunction with eachother, and in terms of their time of administration, either serially orsimultaneously. Thus, the administration of one component agent may beprior to, concurrent with, or subsequent to the administration of theother component agent(s).

The invention also provides pharmaceutical compositions comprising acompound of Formula I or a pharmaceutically acceptable salts or solvatethereof and at least one pharmaceutically acceptable carrier, diluent,excipient and/or adjuvant. As indicated above, the invention also coverspharmaceutical compositions which contain, in addition to a compound ofthe present invention, a pharmaceutically acceptable salts or solvatethereof as active ingredient, additional therapeutic agents and/oractive ingredients.

Another object of this invention is a medicament comprising at least onecompound of the invention, or a pharmaceutically acceptable salts orsolvate thereof, as active ingredient.

According to a further feature of the present invention there isprovided the use of a compound of Formula I or a pharmaceuticallyacceptable salts or solvate thereof for the manufacture of a medicamentfor modulating NK-3 receptor activity in a patient, in need of suchtreatment, which comprises administering to said patient an effectiveamount of compound of the present invention, or a pharmaceuticallyacceptable salts or solvate thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

As set forth above, the compounds of the invention, theirpharmaceutically acceptable salts or solvates may be used in monotherapyor in combination therapy. Thus, according to one embodiment, theinvention provides the use of a compound of the invention for themanufacture of a medicament for at least one of the purposes describedabove, wherein said medicament is administered to a patient in needthereof, preferably a warm-blooded animal, and even more preferably ahuman, in combination with at least one additional therapeutic agentand/or active ingredient. The benefits and advantages of such a multipledrug regimen, possible administration regimens as well as suitableadditional therapeutic agents and/or active ingredients are thosedescribed above.

Generally, for pharmaceutical use, the compounds of the invention may beformulated as a pharmaceutical preparation comprising at least onecompound of the invention and at least one pharmaceutically acceptablecarrier, diluent, excipient and/or adjuvant, and optionally one or morefurther pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for topical administration (including ocular), foradministration by inhalation, by a skin patch, by an implant, by asuppository, etc. Such suitable administration forms—which may be solid,semi-solid or liquid, depending on the manner of administration—as wellas methods and carriers, diluents and excipients for use in thepreparation thereof, will be clear to the skilled person; reference ismade to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes,lotions, soft and hard gelatin capsules, suppositories, drops, sterileinjectable solutions and sterile packaged powders (which are usuallyreconstituted prior to use) for administration as a bolus and/or forcontinuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other substances that are commonly used inpharmaceutical formulations, such as lubricating agents, wetting agents,emulsifying and suspending agents, dispersing agents, desintegrants,bulking agents, fillers, preserving agents, sweetening agents, flavoringagents, flow regulators, release agents, etc. The compositions may alsobe formulated so as to provide rapid, sustained or delayed release ofthe active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Generally, such unit dosageswill contain between 0.05 and 1000 mg, and usually between 1 and 500 mg,of the at least one compound of the invention, e.g. about 10, 25, 50,100, 200, 300 or 400 mg per unit dosage.

Usually, depending on the condition to be prevented or treated and theroute of administration, the active compound of the invention willusually be administered between 0.01 to 100 mg per kilogram, more oftenbetween 0.1 and 50 mg, such as between 1 and 25 mg, for example about0.5, 1, 5, 10, 15, 20 or 25 mg, per kilogram body weight of the patientper day, which may be administered as a single daily dose, divided overone or more daily doses, or essentially continuously, e.g. using a dripinfusion.

Definitions

The definitions and explanations below are for the terms as usedthroughout the entire application, including both the specification andthe claims.

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless indicatedotherwise.

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.Preferred halo groups are fluoro and chloro. The most preferred halogroup is fluoro in the present invention unless otherwise indicatedherein.

The term “alkyl” by itself or as part of another substituent refers to ahydrocarbyl radical of formula C_(n)H_(2n+1) wherein n is a numbergreater than or equal to 1. Generally, alkyl groups of this inventioncomprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms.Alkyl groups may be linear or branched.

Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl and t-butyl.

The term “haloalkyl” alone or in combination, refers to an alkyl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen as defined above. Non-limiting examples of suchhaloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.C_(x-y)-haloalkyland Cx-Cy-alkyl refer to alkyl groups which comprisefrom x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl,trifluoromethyl.

The term “alkenyl” as used herein refers to an unsaturated hydrocarbylgroup, which may be linear or branched, comprising one or morecarbon-carbon double bonds. Suitable alkenyl groups comprise between 2and 3 carbon atoms. Examples of alkenyl groups are ethenyl (vinyl),2-propenyl (allyl). The preferred alkenyl group herein is the vinylgroup.

The term “thiophen-2-yl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The term “cycloalkyl” as used herein is a cyclic alkyl group, that is tosay, a monovalent, saturated, or unsaturated hydrocarbyl group having 1or 2 cyclic structures. Cycloalkyl includes monocyclic hydrocarbylgroups only. Cycloalkyl groups may comprise 3 or more carbon atoms inthe ring and generally, according to this invention comprise from 3 to4, more preferably 3 carbon atoms. Examples of cycloalkyl groups includecyclopropyl and cyclobutyl, with cyclopropyl being particularlypreferred.

The term “ester” or “esters” as used herein means a group selected thegroup consisting of unsubstituted C1-C4 alkyloxycarbonyl, unsubstitutedphenyloxycarbonyl or unsubstituted phenyl(C1-C2 alkyl)oxycarbonyl.

Suitable ester groups include methyloxycarbonyl, ethyloxycarbonyl,n-propyloxycarbonyl, i-propyloxycarbonyl, n-butyloxycarbonyl,i-butyloxycarbonyl, s-butyloxycarbonyl, t-butyloxycarbonyl,phenyloxycarbonyl, benzyloxycarbonyl and phenethyloxycarbonyl, amongwhich methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl,i-propyloxycarbonyl, phenyloxycarbonyl, and benzyloxycarbonyl arepreferred.

The ring atoms of 5,6,7,(8-substituted)-[1,2,4]triazolo[4,3-a]pyrazinesof the invention are numbered based on scheme below.

Bonds from an asymmetric carbon in compounds are generally depictedusing a solid line (-), a zigzag line (

), a solid wedge (

), or a dotted wedge (

). The

use of either a solid or dotted wedge to depict bonds from an asymmetriccarbon atom is meant to indicate that only the stereoisomer shown ismeant to be included.

In the compounds of the invention, a dotted wedge (

). carrying a methyl at the C8 position is used to depict the(R)-enantiomer. A solid wedge (

) would be used to depict the (S)-enantiomer.

The compounds of Formula II and subformulae thereof contain astereogenic carbon center at position 8 and thus may exist as (R)- and(S)-enantiomers. The use of a solid line to depict the bond betweenposition 8 of the ring and R^(1′) with a star next to position 8indicates that the individual enantiomers are meant, thus excludingracemic mixtures thereof.

A solid wedge (

) for the bond between position 8 of the ring and R^(1′) is used todepict the (S)-enantiomer and a dotted wedge (

) for the bond between position 8 of the ring and R^(1′) is used todepict the (R)-enantiomer.

For instance,(R)-8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineis depicted as . . .

Prototropic tautomer equilibrium form may exist in certain compounds ofFormula I″′ thereby engendering either or both tautomers to exist; anexample is illustrated below.

All tautomeric forms of compounds of the invention fall, whereverapplicable, within the scope of the invention regardless of whichspecific tautomer is drawn or named.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts of the compounds ofFormulae I, II and III include the acid addition salts thereof. Suitableacid addition salts are formed from acids which form non-toxic salts.Examples include the acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts.

The compounds of Formulae I, II or III of the invention may be preparedin salt form through the use of salt-formers. Suitable acids arepreferably but not limited to those that are considered to formpharmaceutically acceptable salts (see for example: Wermuth, C. G.;Stahl, P. H. In “Handbook of Pharmaceutical Salts”, Wiley-VCH: New York,2002). Such salts may be formed to enhance chemical purity and/orenhance storage lifetime of the attendant salt intermediate. Examples ofrelevant salt-formers as aforementioned include in a non-limiting sensethe following acids; through any and all stereoisomeric forms whereapplicable: HCl, sulfuric acid, phosphoric acid, acetic acid,ethanesulfonic acid, citric acid, lactic acid, maleic acid, mandelicacid, succinic acid, phenylpropionic acid, p-toluenesulfonic acid.Preferred salt-formers include HCl.

Pharmaceutically acceptable salts of compounds of Formulae I, II and IIImay be prepared by one or more of these methods:

(i) by reacting the compound of Formulae I, II or III with the desiredacid;

(ii) by removing an acid-labile protecting group from a suitableprecursor of the compound of Formulae I, II or III; or

(iii) by converting one salt of the compound of Formulae I, II or III toanother by reaction with an appropriate acid or by means of a suitableion exchange column.

The term “solvate” is used herein to describe a compound in thisinvention that contains stoichiometric or sub-stoichiometric amounts ofone or more pharmaceutically acceptable solvent molecule such asethanol. The term “hydrate” refers to when the said solvent is water.

All references to compounds of Formulae I, II or III include referencesto salts, solvates, multi-component complexes and liquid crystalsthereof.

The compounds of the invention include compounds of Formulae I, II orIII as hereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs, prodrugs and tautomers thereof andisotopically-labeled compounds of Formulae I, II or III.

In addition, although generally, with respect to the salts of thecompounds of the invention, pharmaceutically acceptable salts arepreferred, it should be noted that the invention in its broadest sensealso included non-pharmaceutically acceptable salts, which may forexample be used in the isolation and/or purification of the compounds ofthe invention. For example, salts formed with optically active acids orbases may be used to form diastereoisomeric salts that can facilitatethe separation of optically active isomers of the compounds of FormulaeI, II or III above.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the compounds of Formulae I, II or III.

The term “prodrug” as used herein means the pharmacologically acceptablederivatives of compounds of Formulae I, II or III, such as for exampleesters, whose in vivo biotransformation product generates thebiologically active drug. Prodrugs are generally characterized byincreased bio-availability and are readily metabolized into biologicallyactive compounds in vivo.

The term “predrug”, as used herein, means any compound that will bemodified to form a drug species, wherein the modification may take placeeither inside or outside of the body, and either before or after thepredrug reaches the area of the body where administration of the drug isindicated.

The term “patient” refers to a warm-blooded animal, more preferably ahuman, who/which is awaiting the receipt of, or is receiving medicalcare or is/will be the object of a medical procedure.

The term “human” refers to a subject of both genders and at any stage ofdevelopment (i.e. neonate, infant, juvenile, adolescent, adult).

The terms “treat”, “treating” and “treatment, as used herein, are meantto include alleviating, attenuating or abrogating a condition or diseaseand/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention”, as used herein,refer to a method of delaying or precluding the onset of a condition ordisease and/or its attendant symptoms, barring a patient from acquiringa condition or disease, or reducing a patient's risk of acquiring acondition or disease.

The term “therapeutically effective amount” (or more simply an“effective amount”) as used herein means the amount of active agent oractive ingredient (e.g. NK-3 antagonist) that is sufficient to achievethe desired therapeutic or prophylactic effect in the patient towhich/whom it is administered.

The term “administration”, or a variant thereof (e.g., “administering”),means providing the active agent or active ingredient (e. g. a NK-3antagonist), alone or as part of a pharmaceutically acceptablecomposition, to the patient in whom/which the condition, symptom, ordisease is to be treated or prevented.

By “pharmaceutically acceptable” is meant that the ingredients of apharmaceutical composition are compatible with each other and notdeleterious to the patient thereof.

The term “antagonist” as used herein means a compound that competitivelyor non-competitively binds to a receptor at the same site as an agonist(for example, the endogenous ligand) and does not activate anintracellular response initiated by an active form of the receptor. Anantagonist for a specific receptor, therefore, inhibits theintracellular response induced by an agonist to that specific receptor.

The term “sex hormone-dependent disease” as used herein means a diseasewhich is exacerbated by, or caused by, excessive, inappropriate orunregulated sex hormone production. Examples of such diseases in meninclude but are not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carninoma, testicularcancer, androgen dependent acne, male pattern baldness and precociouspuberty in boys. Examples of such diseases in women include but are notlimited to endometriosis, abnormal puberty, uterine fibrosis, uterinefibroid tumor, hormone-dependent cancers (ovarian cancer, breastcancer), androgen-producing tumor (virilizing ovarian or adrenal tumor),hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome(PCOS), premenstrual dysphoric disease (PMDD), HAIR-AN syndrome(hyperandrogenism, insulin resistance and acanthosis nigricans), ovarianhyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells inovarian stroma), other manifestations of high intraovarian androgenconcentrations (e.g. follicular maturation arrest, atresia, anovulation,dysmenorrhea, dysfunctional uterine bleeding, infertility), menorrhagiaand adenomyosis (abnormal endometrial growth within the muscle of theuterus).

The term “Psychotic disorders” as used herein means a group of illnessesthat affect the mind. These illnesses alter a patient's ability to thinkclearly, make good judgments, respond emotionally, communicateeffectively, understand reality, and behave appropriately. When symptomsare severe, patient with psychotic disorders have difficulty staying intouch with reality and are often unable to meet the ordinary demands ofdaily life. Psychotic disorders include but are not limited to,schizophrenia, schizophreniform disorder, schizo-affective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition,substance-induced psychotic disorder or psychotic disorders nototherwise specified (Diagnostic and Statistical Manual of MentalDisorders, Ed. 4th, American Psychiatric Association, Washington, D.C.1994).

The term “pharmaceutical vehicle” as used herein means a carrier orinert medium used as solvent or diluent in which the pharmaceuticallyactive agent is formulated and/or administered. Non-limiting examples ofpharmaceutical vehicles include creams, gels, lotions, solutions, andliposomes.

The expression “reagent resulting in a N-sp³ protective group (PG) onthe amine nitrogen of the compound of Formula A” means any such reagentsthat result in a cleavable protective group substitution(s) whileretaining the protected nitrogen atom as a tertiary amine, i.e. in theN-sp³ hybridized form. Specifically N-benzyl and in particularelectron-rich substituted N-benzyl; especially N-benzyl substituted byone or more electron donating groups, such as for example alcoholgroups, alkoxy groups (especially methoxy), amino groups, alkyl groups;are considered embodiments of the “N-sp³ protective group” definitionabove. Examples of such reagents include, but are not limited to,benzaldehyde, 4-methoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, and2,4,6-trimethoxybenzaldehyde. Examples of N-benzyl or electron-richsubstituted N-benzyl protective groups include, but are not limited toN-benzyl, N-4-methoxybenzyl, N-3,4-dimethoxybenzyl, N-3-methoxybenzyl,N-3,5-dimethoxybenzyl, N-2,4,6-trimethoxybenzyl. (See Wuts, P. G. M.;Greene, T. W. In “Greene's Protective Groups in Organic Synthesis”,Wiley-Interscience: New York, 4^(th) Edition, Chap. 7, pp. 696-926, andKocieński, P. J. In “Protecting Groups”, Georg Thieme Verlag: Stuttgart,N.Y.; 3^(rd) Edition, Chap. 8, pp. 487-643).

The present invention will be better understood with reference to thefollowing examples. These examples are intended to representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows X-ray crystal structure of compound no. 1 (thermaldisplacement ellipsoids drawn at the 50% probability level).

FIG. 2 shows X-ray crystal structure of compound no. 19 (thermaldisplacement ellipsoids drawn at the 50% probability level).

FIG. 3 shows the effects of a single intravenous 10 mg/kg dose ofcompound no. 1 on lutenizing hormone (‘LH’) plasma levels in castratedmale, Sprague-Dawley rats measured 1 hour after dosing. LH levels areexpressed as means±S.E.M. The vehicle is 9%2-hydroxypropyl-β-cyclodextrin/H₂O (w/w). Vehicle, N=10 rats; Compoundno. 1, N=9 rats.

FIG. 4 shows the effects of a single intravenous 10 mg/kg dose ofcompound no. 19 on lutenizing hormone (‘LH’) plasma levels in castratedmale, Sprague-Dawley rats measured 1 hour after dosing. LH levels areexpressed as means±S.E.M. The vehicle is 9%2-hydroxypropyl-β-cyclodextrin/H2O (w/w). Vehicle, n=5 rats; Compoundno. 19, n=5 rats.

FIG. 5 shows the effects of a single intravenous 50 mg/kg dose ofcompound no. 1 on testosterone plasma levels in male, Sprague-Dawleyrats. N=3 rats per treatment group. Testosterone levels were measuredjust prior to dosing and at times 1, 5, 15, 90, 150, 210 min afterdosing to derive a time-response curve. Data are expressed as thetestosterone area under the curve (‘AUC’)±S.E.M. The vehicle is 9%2-hydroxypropyl-β-cyclodextrin/H₂O (w/w).

EXAMPLES Chemistry Examples

All reported temperatures are expressed in degrees Celsius (° C.); allreactions were carried out at room temperature (RT) unless otherwisestated.

All reactions were followed by thin layer chromatography (TLC) analysis(TLC plates, silica gel 60 F₂₅₄, Merck) was used to monitor reactions,establish silica-gel flash chromatography conditions. All other TLCdeveloping agents/visualization techniques, experimental set-up orpurification procedures that were used in this invention, when notdescribed in specific details, are assumed to be known to thoseconversant in the art and are described in such standard referencemanuals as: i) Gordon, A. J.; Ford, R. A. “The Chemist's Companion—AHandbook of Practical Data, Techniques, and References”, Wiley: NewYork, 1972; ii) Vogel's Textbook of Practical Organic Chemistry, PearsonPrentice Hall: London, 1989.

HPLC-MS spectra were typically obtained on an Agilent LCMS usingelectropsray ionization (ESI). The Agilent instrument includes anautosampler 1200, a binary pump 1100, an ultraviolet multi-wavelengthdetector 1100 and a 6100 single-quad mass-spectrometer. Thechromatography column used was Sunfire 3.5 μm, C18, 3.0×50 mm indimensions.

Eluent typically used was a mixture of solution A (0.1% TFA in H₂O) andsolution B (0.1% TFA in MeCN).

Gradient was applied at a flow rate of 1.3 mL per minute as follows:gradient A: held the initial conditions of 5% solution B for 0.2 min,increased linearly to 95% solution B in 6 min, held at 95% during 1.75min, returned to initial conditions in 0.25 min and maintained for 2.0min; gradient B: held the initial conditions of 5% solution B for 0.2min, increased linearly to 95% in 2.0 min, held at 95% during 1.75 min,returned to initial conditions in 0.25 min and maintained for 2 min.

Determination of chiral purity was made using chiral HPLC that wasperformed on an Agilent 1100 (binary pump and a ultraviolet multiwavelength detector) with manual or automatic (Autosampler 1100)injection capabilities. Columns used were CHIRALPAK IA 5 μm, 4.6×250 mmor CHIRALPAK IB 5 μm, 4.6×250 mm in isocratic mode. Choice of eluent waspredicated on the specifics of each separation. Further detailsconcerning the chiral HPLC methods used are provided below.

Method A: column CHIRALPAK IA 5 μm, 4.6×250 mm, eluent: EtOAc plus 0.1%of DEA, flow rate: 1.0 mL per minute; UV detection at 254 nm; column atRT, eluent was used as sample solvent.

Method A′: column CHIRALPAK IA 5 μm, 4.6×250 mm, eluent: EtOAc plus 0.1%of DEA, flow rate: 1.5 mL per minute; UV detection at 254 nm; column atRT, eluent was used as sample solvent.

Method B: column CHIRALPAK IA 5 μm 4.6×250 mm, eluent:hexane/isopropanol/dichlormethane (3:1:1 v/v) plus 0.1% of DEA, flowrate: 1.0 mL per minute; UV detection at 254 nm, column at RT, eluentwas used as sample solvent.

Method B′: column CHIRALPAK IA 5 μm 4.6×250 mm, eluent:hexane/isopropanol/dichlormethane (3:1:1 v/v) plus 0.1% of DEA, flowrate: 1.5 mL per minute; UV detection at 254 nm, column at RT, eluentwas used as sample solvent.

Method C: column CHIRALPAK IB 5 μm 4.6×250 mm, eluent: hexane/ethanol(7:3 v/v) plus 0.1% of DEA, flow rate: 1.0 mL min⁻¹, mL per minute; UVdetection at 254 nm, column at RT, eluent was used as sample solvent.

Method C′: column CHIRALPAK IA 5 μm 4.6×250 mm, eluent: hexane/ethanol(1:1 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detectionat 254 nm, column at RT, eluent was used as sample solvent.

Preparative HPLC purifications were typically carried out on a WatersFractionLynx instrument. This instrument consists of a fractioncollector, a 2767 sample manager, a pump control a module II, a 515 HPLCpump, a 2525 binary gradient module, a switching valve, a 2996photodiode array detector and a Micromass ZQ mass spectrometer. Thechromatography column used was Waters Sunfire 5 μm, C18, 19×100 mm, orXBridge 5 μm, C18, 19×100 mm depending on the type of eluent systememployed, i.e. low pH or high pH conditions.

For high-pH HPLC purifications, eluent typically consisted of a mixtureof solution A (0.04 M ammonium bicarbonate in H₂O plus 0.1% of conc.NH₄OH) and solution B was MeCN. The gradient was adapted depending onthe impurity profile in each sample purified, thereby allowingsufficient separation between the impurities and the desired compound.

Chiral preparative HPLC purifications were performed on an Agilent 1200instrument (preparative pump 1200 and ultraviolet multi wavelengthdetector 1200) with manual injection. The chiral columns used are asfollows: CHIRALPAK IA 5 μm, 20×250 mm, CHIRALPAK IA 5 μm, 10×250 mm or aCHIRALPAK IB 5 μm, 10×250 mm. All chiral HPLC methods were employed inan isocratic mode. The eluent mixture was selected based on theanalytical chiral HPLC experiment (see above) that provided the bestchiral separation.

¹H (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded on a BrukerAvance DRX 300 instrument. Chemical shifts are expressed in parts permillion, (ppm, δ units). Coupling constants are expressed in Hertz (Hz).Abbreviations for multiplicities observed in NMR spectra are as follows:s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br(broad).

Solvents, reagents and starting materials were purchased and used asreceived from commercial vendors unless otherwise specified.

The following abbreviations are used:

-   Boc: tert-butoxycarbonyl,-   Cpd: compound,-   DCM: Dichloromethane,-   DEA: diethylamine,-   DMA: N,N-dimethylaceetamide,-   DMB: 2,4-dimethoxybenzyl,-   DMB-CHO: 2,4-dimethoxybenzaldehyde,-   DMF: N,N-dimethylforrnarnide,-   ee: Enantiomeric excess,-   eq: Equivalent(s),-   Et: Ethyl,-   EtOAc: Ethyl acetate,-   EtOH: Ethanol,-   g: Gram(s),-   h: Hour(s),-   IPA: isopropanol,-   L: Liter(s),-   MeOH: Methanol,-   μL: Microliter(s),-   mg: Milligram(s),-   mL: Milliliter(s),-   mmol: Millimole(s),-   min: Minute(s),-   NMM: N-methylmorpholine-   P: UV purity at 254 nm or 215 nm determined by HPLC-MS,-   PMB: 4-methoxybenzyl,-   PMB-CHO: 4-methoxybenzaldehyde,-   RT: Room temperature,-   tBu: tert-Butyl,-   TFA: trifluoroacetic acid,-   THF: Tetrahydrofuran,-   TLC: Thin layer chromatography,-   TMS: trimethylsylil,-   Y: Yield.

The intermediates and compounds described below were named usingChemDraw® Ultra version 12.0 (CambridgeSoft, Cambridge, Mass., USA).

I. Racemic Synthesis I.1. General Synthetic Scheme for Racemic Synthesis

Most compounds of the invention were synthesized using the methodologydescribed in Scheme 1, which represents the racemic product synthesis.The racemic products were subjected to chiral HPLC for chiralseparation.

The general synthetic scheme comprises the following steps:

Step 1: Ketopiperazine 1.1 was protected and converted to iminoether 1by using the Meerwein reagent (Et₃OBF₄).

Step 2: Ester 2.2 was subsequently converted to acyl hydrazide 2. Ester2.2 may be obtained be esterification of acid 2.1.

Step 3: Cyclodehydration between the acyl hydrazide 2 and the iminoether1 furnished the protected triazolopiperazine 3.1. Thereafter, 3.1 wassubjected to acidolytic deprotection to obtain 3.

Step 4: The thus obtained triazolopiperazine intermediate 3 was acylatedthrough reaction with the appropriate acid chloride 4.1 to obtain theracemic final target structure represented by the general Formula 4. Thechiral final compounds were subsequently obtained by purification usingpreparative chiral HPLC.

I.2. Step 1: Protection and Conversion to Iminoether 1

Method A: Boc Protection and Conversion to Iminoether 1

Method A is the procedure used for the synthesis of the iminoetherintermediates 1 with a Boc protection and is detailed below:

Method A is illustrated by the synthesis of intermediates 1a and 1bwherein R1 is H and Me respectively.

Synthesis of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1 (2H)-carboxylate1a

To a pre-made solution of triethyloxonium tetrafluoroborate (2.3 g,0.012 mol) in anhydrous DCM (20 mL) was added 1.2a (2 g, 0.01 mol) at 0°C. After the addition was completed, the ice-bath was removed, and thereaction mixture was allowed to warm to RT and stirred for an additionalhour (reaction progress monitored by LCMS). Upon completion of thereaction, a saturated solution of NaHCO₃ (500 mL) was slowly added tothe reaction mixture and it was stirred for 5 min. The organic layer wasseparated and the aqueous layer was further extracted with DCM (200 mL).The combined organic layers were subsequently washed with brine, driedover MgSO₄, filtered and further dried in vacuo to obtain the titleintermediate 1a as viscous yellow oil. Yield: 2.03 g (88%). ¹H NMR(CDCl₃): δ: 4.1 (q, J=7.1, 2H), 3.85 (s, 2H), 3.5 (m, 1H), 3.35 (t,J=5.1, 2H), 1.45 (s, 9H), 1.3 (t, J=7.1, 3H).

Synthesis of tert-butyl3-ethoxy-2-methyl-5,6-dihydropyrazine-1(2H)-carboxylate 1b

Step 1: Synthesis of tert-butyl 2-methyl-3-oxopiperazine-1-carboxylate1.2b

NEt₃ (20 mL, 145 mmol) was added to a solution of3-methylpiperazin-2-one 1.1b (15 g, 131 mmol) in anhydrous DCM (200 mL)under N₂ at RT. After 10 min stirring, the reaction mixture was cooledto 0° C. and Boc₂O (33 g, 151 mmol). The reaction mixture was stirred atRT for 1 h and thereupon washed with 0.5M HCl (150 mL), brine (150 mL),dried over MgSO₄, filtered and concentrated to constant weightfurnishing 2.2 as yellow oil (20.2 g, 72%). LCMS: P=100%, retentiontime=2.0 min, (M+H-tBu)⁺: 159

Step 2: Synthesis of tert-butyl3-ethoxy-2-methyl-5,6-dihydropyrazine-1(2H)-carboxylate 1b

To a solution of 1.2b (24 g, 87 mol) in anhydrous DCM (250 mL) at 0° C.under N2 atmosphere was added a pre-made solution of triethyloxoniumtetrafluoroborate (19.92 g, 105 mmol) in anhydrous DCM (50 mL). Thereaction mixture was allowed to warm to RT and stirred for 30 minwhereupon saturated solution of NaHCO₃ (400 mL) was added. The extractedaqueous layer was then washed with DCM (200 ml) and the combined organicextracts were subsequently washed with brine (300 mL), dried over MgSO₄,filtered and further dried in vacuo to obtain the title intermediate 1bas colorless oil. (20.7 g, 98%). LCMS: P=98%, retention time=1.8 min,(M+H+H₂O)⁺: 261; ¹H-NMR (CDCl₃): δ 4.30 (br, 1H), 4.11-4.01 (m, 2H),3.84 (br, 1H), 3.48-3.40 (m, 2H), 2.90 (br, 1H), 1.32 (d, J=6.9, 3H),1.26 (t, J=7.1, 3H).

Method B: Protection Using Benzyl Derivative Protecting Groups Such asDMB and Conversion to Iminoether 1

Method B is the procedure used for the synthesis of the iminoetherintermediates 1 with a benzyl derivative protecting group such as DMBand is detailed below:

Method B is illustrated by the synthesis of intermediates 1c and 1dwherein R1 is Me and the protecting group is DMB and PMB respectively.

Synthesis of1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine 1c

Step 1: Synthesis 4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one 1.2c

In a round-bottom flask, were sequentially introduced3-methylpiperazin-2-one (10 g, 88 mmol), 2,4-dimethoxybenzaldehyde (16g, 96 mmol), acetic acid (6.5 ml, 114 mmol) and sodiumtriacetoxyborohydride (22.3 g, 105 mmol) in commercial anhydrousacetonitrile (750 mL), at RT, under N₂ atmosphere. The reaction wasstirred at RT overnight. The reaction mixture was quenched carefully at0° C. with saturated NaHCO₃ solution (100 mL) until no more bubbling wasobserved. Aqueous and organic layers were separated. The aqueous layerwas extracted with EtOAc (3×300 mL) and the combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated underreduced pressure to afford the title compound as yellow oil. The crudecompound was then purified on silica gel (DCM/MeOH: 98/2 to 95/5) toafford the desired product 1.2c as a pale yellow oil (20.6 g, 78 mmol,89%). LCMS: P=97%, retention time=1.6 min, (M+H)⁺: 265.

In the case of PMB and TMB protection, 4-methoxybenzaldehyde or2,4,6-trimethoxybenzaldehyde was used instead of2,4-dimethoxybenzaldehyde to furnish4-(4-methoxybenzyl)-3-methylpiperazin-2-one or 4-(2,4,6-trimethoxybenzyl)-3-methylpiperazin-2-one.

Step 2:1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine 1c

Oven-dried (115° C.) sodium carbonate (18.6 g, 98 mmol, 2.25 eq.) wasplaced in a 500 mL round-bottom flask. The round-bottom flask wasbackfilled with Ar and then capped with a rubber septum. A solution of4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one 1.2c (20.6 g, 78 mmol, 1eq.) in anhydrous DCM (250 mL) was added, followed by triethyloxoniumtetrafluoroborate (18.6 g, 98 mmol, 1.25 eq.) in one portion.Thereafter, the reaction mixture was stirred further at RT for 1 hwhereupon the reaction mixture was diluted with water (250 mL). Theaqueous layer was extracted with DCM (3×150 mL). The organic layers werecombined, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude compound was then purified on silica gel (EtOAc) toafford the desired product 1c as orange oil. Yield: 13.2 g, 58%.

LCMS: P=93%, retention time=1.8 min, (M+H+H₂O)⁺: 311; ¹H-NMR (CDCl₃): δ7.23 (d, J=8.8 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 6.44 (s, 1H), 4.02 (m,2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (d, J_(AB)=14.0 Hz, 1H), 3.46 (d,J_(AB)=14.0 Hz, 1H), 3.44 (m, 2H), 3.10 (m, 1H), 2.79 (m, 1H), 2.32 (m,1H), 1.35 (d, J=6.8 Hz, 3H), 1.24 (t, J=6.0 Hz, 3H).

Starting step 2 from 4-(4-methoxybenzyl)-3-methylpiperazin-2-one allowedto isolate1-(4-methoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine 1d.LCMS: P=95%, retention time=1.8 min, (M+H+H₂O)⁺: 281.

I.3. Step 2: Formation of acyl hydrazide 2

Method C: acyl hydrazide2

Method C is the procedure used for the synthesis of the acyl hydrazides2 and is detailed below:

Method C is illustrated by the synthesis of intermediate 2a, 2k and 2r.

Synthesis of 2-methylthiazole-4-carbohydrazide 2a

In a 100 mL round-bottom flask equipped with a condenser, ethyl2-methylthiazole-4-carboxylate 2.2a (10 g, 58.4 mmol, 1 eq.) wasdissolved in anhydrous EtOH (25 mL) and treated at RT with hydrazinemonohydrate (17.0 mL, 354.4 mmol, 6 eq.). The resulting yellow solutionwas heated at reflux temperature for 14 h. After allowing the reactionmixture to come to RT, the solution was concentrated under reducedpressure to afford 13.4 g of a brown oil. Co-evaporations using 3×200 mLof a mixture of commercial anhydrous DCM:MeOH (1:1) were performed toremove residual water. The residue was then recrystallized from hot EtOH(60 mL). The obtained crystals were filtered and washed with cooled (0°C.) EtOH (2×30 mL). The orange solid was dried under vacuum for 1 h toafford 2a. Yield: 5.85 g, 64%. LCMS: P=100%, retention time=0.5 min,(M+H)⁺: 158; ¹H-NMR (CDCl₃): δ 8.32 (br, 1H), 7.96 (s, 1H), 4.07 (br,2H), 2.70 (s, 3H).

In one embodiment 1.2 to 20 equivalents of hydrazine hydrate was used tocarry out this reaction using a temperature range from RT to reflux.

In one embodiment, hydrazide 2 was recrystallized and/or precipitated.

The following intermediates were also prepared from the ad hoccarboxylic acids, methyl or ethyl esters using General Method C:

intermediate 2b: 2-trifluoromethylthiazole-4-carbohydrazide, methylester precursor was previously synthesized using conventionalesterification method (such as TMS-Cl in methanol) from commerciallyavailable acid;

intermediate 2c: 2-ethylthiazole-4-carbohydrazide;

intermediate 2d: 2-vinylthiazole-4-carbohydrazide, tert-butyl2-(4-(hydrazinecarbonyl)thiazol-2-yl)ethylcarbamate was used asprecursor of the vinyl moiety, commercially available ethyl2-(2-aminoethyl)thiazole-4-carboxylate dihydrochloride was previouslyBoc-protected and then esterified using conventional methods;intermediate 2e: 2-methyloxazole-4-carbohydrazide;intermediate 2f: 2-isopropyloxazole-4-carbohydrazide, ethyl esterprecursor was previously synthesized from condensation of isobutyramideand ethyl 3-bromo-2-oxopropanoate according to WO2009/70485 A1;intermediate 2g: 2-cyclopropyloxazole-4-carbohydrazide, ethyl ester wasmade as described above;intermediate 2 h: 2,5-dimethylthiazole-4-carbohydrazide, methyl esterprecursor was previously synthesized using conventional esterificationmethod (such as TMS-Cl in methanol) from commercially available acid;intermediate 2i: tert-butyl(4-(hydrazinecarbonyl)thiazol-2-yl)carbamate, ethyl2-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate precursor waspreviously Boc-protected using conventional method.intermediate 2j: 2-isopropylthiazole-4-carbohydrazide.

Synthesis of 4-methylthiazole-2-carbohydrazide 2k

In a 100 mL round-bottom flask equipped with a condenser,4-methylthiazole-2-carboxylate 2.2k (500 mg, 2.92 mmol, 1 eq.) wasdissolved in anhydrous EtOH (5 mL) and treated at RT with hydrazinemonohydrate (216 μL, 4.46 mmol, 1.5 eq.). The resulting solution washeated at reflux temperature for 18 hours. After allowing the reactionmixture to come to RT, the solution was concentrated under reducedpressure and the obtained crude was purified on a pad of silica (eluent:DCM/MeOH: 100/0 to 97/3) to afford 266 mg of 2k as a white solid (266mg, 1.69 mmol, 57%). LCMS: P=90%, retention time=0.7 min, (M+H)⁺: 158.

The following intermediates were also prepared from the ad hoccarboxylic acids methyl or ethyl esters using General Method C:

Intermediate 2l: 4,5-dimethylthiazole-2-carbohydrazide, prepared fromester 5.3. This latter was prepared in two steps from commercialthiazole 5.1 (procedure adapted from Castells, J. et al., TetrahedronLett., 1985, 26, 5457-5458).

Step 1: Synthesis of 4,5-dimethylthiazole-2-carboxylic acid 2.1l

A solution of 2.01 (3.0 g, 25.7 mmol, 1 eq.) in dry THF (50 mL) wasdegassed using vaccum pump and backfilled with N₂ (repeated threetimes). The solution was then cooled to −78° C. and n-butyllithium (2.5Min hexanes, 11.3 mL, 28.3 mmol, 1.1 eq.) was added. The solution wasstirred for 30 min at −78° C. and then the solution was placed under CO₂atmosphere (bubbling directly into the solution). After 1 hour ofstirring at −78° C., the solution was allowed to warm to roomtemperature. HCl 1N (25 mL) and EtOAc (200 mL) were added. Afterseparation of both phases, the aqueous phase was extracted with DCM(2×100 mL). The organic phases were combined, washed with water, driedover MgsO₄, filtered and concentrated under reduced pressure to affordacid 2.1l (3.0 g, 6.30 mmol) which was used in the next step withoutfurther purification.

Step 2: Synthesis of methyl 4,5-dimethylthiazole-2-carboxylate 2.2l

To a solution of acid 2.1l (3.0 g, 6.30 mmol, 1 eq.) in commercial dryMeOH (12 mL) was added at RT chlorotrimethylsilane (4.0 mL, 31.5 mmol, 5eq.) dropwise. The resulting solution was stirred at 60° C. for 14hours. The reaction mixture was cooled down to RT, diluted with DCM (100mL) and quenched with a saturated solution of NaHCO₃ (50 mL). Theaqueous phase was extracted with DCM (2×50 mL). The organic phases werecombined, washed with brine (100 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude was purified by flashchromatography on silica gel (eluent Pet. Ether/EtOAc: 100/0 to 80/20)to afford 2.2l (1.32 g, 7.7 mmol, 55%). LCMS: P=33%, retention time=2.1min, (M+H)⁺: 172. Intermediate 2m:3-methyl-1,2,4-oxadiazole-5-carbohydrazide, prepared from ester 2.2musing General Method C. This latter was prepared in one step fromacetimidamide 2.0m (adapted from Street Leslie J. et al, J. Med. Chem.,2004, 47(14), 3642-3657).

To a solution of (E)-N′-hydroxyacetimidamide 2.0m (1.0 g, 13.50 mmol, 1eq.) and pyridine (4.35 mL, 54.0 mmol, 4 eq.) in dry DCM (40 mL) wasadded at RT ethyloxalyl chloride (2.4 g, 18.0 mmol, 1.3 eq.). Thesolution was stirred at reflux for 14 hours. The reaction mixture wascooled down to RT and quenched with NH₄Cl sat. (30 mL). The aqueousphase was extracted with DCM (2×50 mL). The organic phases werecombined, washed with NaHCO₃ sat. (50 mL), dried over MgSO₄, filteredand concentrated under reduced pressure to give 2.2m as yellow oil (1.32g, 8.45 mmol, 63%) which was used in the next step without furtherpurification. LCMS: P=92%, retention time=2.0 min, (M+H)⁺: 157.

Intermediate 2n: 3-methyl-1,2,4-thiadiazole-5-carbohydrazide, preparedfrom ester 2.2m using General Method C. This latter was prepared in onestep from acetamide 2.0n, reagents 2.0n′ and 2.0n″ (adapted from U.S.Pat. No. 5,583,092A1).

A solution of 2.0n (500 mg, 8.46 mmol, 1 eq.), and 2.0n′ (820 μL, 9.31mmol, 1.2 eq.) in dry toluene (23 mL) was stirred at reflux for 2 hours.The solvent was then evaporated under reduced pressure and the residuewas dissolved again in toluene (11.3 mL). 2.0n″ (2.0 mL, 25.4 mmol, 3eq.) was added to the solution and the resulting mixture was stirred atreflux for 4 hours. The solvent was evaporated and the obtained crudewas purified by flash chromatography on silica gel (eluent: DCM 100%) toobtain the desired ester 2.2n (150 mg, 0.95 mmol, 11%) as a brown oil.LCMS: P=97%, retention time=1.8 min, (M+H)⁺: 159.

Intermediate 2o: 4-methyloxazole-2-carbohydrazide. Prepared from ester2.2o using General Method C. This latter was prepared in one step from4-methyloxazole 2.0o.

To a solution of 2.0o (1.0 g, 12.0 mmol, 1 eq.) in commercially dry THF(50 mL) was added at −78° C. under Ar atmosphere n-BuLi (2.5M inhexanes, 5.30 mL, 13.24 mmol, 1.1 eq.). After 30 minutes of stirring at−78° C., ethylchloroformate (1.16 mL, 12.13 mmol, 1.0 eq.) was addeddropwise. After 30 minutes of stirring, the dry ice bath was removed andthe resulting solution was allowed to warm to RT and stirred for 14hours. HCl 1N (15 mL) and EtOAc (30 mL) were added. After separation ofboth phases, the aquous phase was extracted with DCM (2×10 mL). Theorganic phases were combined, washed with brine (20 mL), dried overMgsO₄, filtered and concentrated under reduced pressure. The obtainedcrude was purified by flash chromatography on silica gel (eluent:DCM/MeOH: 100/0 to 99.5/0.5) to afford ester 2.2o (240 mg, 1.55 mmol,13%) as a colorless oil. LCMS: P=96%, retention time=2.0 min, (M+H)⁺:156.

Intermediate 2p: 3-isopropyl-1,2,4-thiadiazole-5-carbohydrazide,prepared from ester 2.2p using General Method C. This latter wasprepared in one step from isobutyramide 2.0p, reagents 2.0p′ and 2.0p″as depicted below.

A solution of 2.0p (500 mg, 5.74 mmol, 1 eq.), and 2.0p′ (555 μL, 6.31mmol, 1.2 eq.) in dry toluene (15 mL) was stirred at reflux for 2 hours.The solvent was then evaporated under reduced pressure and the residuewas dissolved again in toluene (7.6 mL). 2.0p″ (900 μL, 11.34 mmol, 2eq.) was added to the solution and the resulting mixture was stirred atreflux for 4 hours. The solvent was evaporated and the obtained crude2.2p (587 mg, 3.15 mmol, 55%) was used in the next step without furtherpurification. LCMS: P=45%, retention time=2.3 min, (M+H)⁺: 187.

Intermediate 2q: 1,3-dimethyl-1H-pyrazole-5-carbohydrazide was preparedfrom commercial ethyl ester using General Method C.

Synthesis of 6-methylpicolinohydrazide 2r

Step 1: Synthesis of methyl 6-methylpicolinate 2.2r

To a solution of 6-methylpicolinic acid 2.1r (3 g, 21.88 mmol) inanhydrous MeOH (70 mL) at RT under N₂ atmosphere was added TMS-Cl (13.88mL, 109 mmol). The reaction mixture was left stirring at 60° C.overnight whereupon the mixture was concentrated under reduced pressureto afford 5.51 g of yellow oil used without further purification in nextstep. LCMS: P=95%, retention time=1.02 min, (M+H)⁺: 152.

Step 2: Synthesis of 6-methylpicolinohydrazide 2r

To a solution of crude methyl 6-methylpicolinate 2.2r (5.51 g, 21.88mmol) in EtOH (22 mL) at RT was added hydrazine monohydrate (10.61 mL,219 mmol). The reaction mixture was heated to reflux for 90 min. Afterallowing the reaction mixture to reach RT, the solution was concentratedunder reduced pressure and purified by silica gel chromatography(eluent: DCM/MeOH: 100/0 to 96/4) to afford the desired product 2r aswhite solid (2.34 g, 15.48 mmol, 71%). LCMS: P=100%, retention time=0.54min, (M+H)⁺: 152.

In one embodiment 2.5 to 20 equivalents of hydrazine hydrate was used tocarry out this reaction using a temperature range from RT to reflux.

In one embodiment, hydrazide 2 was recrystallized and/or precipitated.The following intermediates were also prepared from the ad hoccarboxylic acids or carboxylic acid ethyl ester using General Method C:

intermediate 2s: 6-hydroxypicolinohydrazide,

intermediate 2t: 6-bromopicolinohydrazide.

I.4. Step 3: Cyclodehydration Leading to Triazolopiperazine 3

Method D: Cyclodehydration and Acydolysis-Boc Protection

Method D is the procedure used for the synthesis of thetriazolopiperazine 3 and is detailed below:

Method D is illustrated by the synthesis of intermediates 3a, 3f and 3gwherein the protecting group is Boc.

Synthesis of2-methyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazolehydrochloride 3a

Step 1: Synthesis of tert-butyl8-methyl-3-(2-methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate3.1a

In a 100 mL round-bottom flask equipped with a condenser, imino-ether 1b(1.089 g, 4.77 mmol, 1 eq.) was dissolved in commercial anhydrous EtOH(20 mL), to which was added 2-methylthiazole-4-carbohydrazide 2a (750mg, 4.77 mmol, 1 eq.) in one portion. The resulting solution was stirredunder reflux overnight. The reaction mixture was cooled down to RT andthe solvent was removed under reduced pressure. The crude compound wasthen purified on silica gel (DCM/MeOH: 99/1 to 98/2) to afford thedesired product 3.1a as white solid (1.07 g, 3.33 mmol, 70%). LCMS:P=100%, retention time=2.1 min, (M+H)⁺: 321.

Step 2 Synthesis of2-methyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazolehydrochloride3a

HCl 4M solution in 1,4-dioxane (8.32 mL, 33.3 mmol) was added in oneportion to a solution of 3.1a (1.07 g, 3.33 mmol) in commercialiso-propanol (20 mL). The reaction mixture was stirred at 60° C. After1.5 h (complete conversion by LC-MS), the reaction mixture was allowedto cool to room temperature and then further cooled to 0° C. with an icebath. Thereupon, 10 mL of Et₂O was added. After 15 min stirring, theprecipitate was filtered and dried in vacuo to afford 3a as white solid.Yield: 736 mg (86%).

LCMS: P=97%, retention time=0.5 min, (M+H)⁺: 222.

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method D:

intermediate 3b:4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(trifluoromethyl)thiazolehydrochloride, from intermediates 1a and 2b;

intermediate 3c:4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-vinylthiazole,from intermediates 1a and 2d then the Boc aminoethyl derivative obtained3.1c was deprotected in acidic conditions (as step 2 above using only 2eq of HCl in dioxane) followed by dimethylamine elimination (using 10 eqof NaH and MeI at RT), then vinyl derivative 3.1c obtained was subjectedto step 2 above to afford 3c;intermediate 3d:4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-isopropyloxazolehydrochloride, from intermediates 1a and 2f;intermediate 3e:2-isopropyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazolehydrochloride, from intermediates 1a and 2j.

Synthesis of4-methyl-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3f

Step 1: Synthesis of tert-butyl3-(4-methylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate3.1f

Imino-ether 1a (148 mg, 0.649 mmol, 1 eq.) was dissolved in anhydrousEtOH (3 mL) at RT, to which was added 2-methylthiazole-4-carbohydrazide2k (102 mg, 0.649 mmol, 1 eq.). The resulting solution was stirred underreflux overnight. The reaction mixture was cooled to RT and the solventwas removed under reduced pressure. The crude compound was then purifiedon silica gel (DCM/MeOH: 99/1 to 98/2) to afford the desired product3.1f as yellow solid (174 mg, 83%). LCMS: P=93%, retention time=2.2 min,(M+H)⁺: 322.

Step 2 Synthesis of2-methyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazolehydrochloride3f

4M HCl in dioxane (2.71 mL, 10.83 mmol) was added to a solution ofBoc-triazolopiperazine 3.1f (1.07 g, 3.33 mmol) in iso-propanol (3 mL)at RT. The reaction mixture was stirred at 60° C. After 1.5 h (completeconversion by LC-MS), the reaction mixture was allowed to cool to roomtemperature and then further cooled to 0° C. with an ice bath.Thereupon, 5 mL of Et₂O was added. After 30 min stirring, theprecipitate was filtered off and dried in vacuo to afford 3f as a whitesolid (132 mg, 95%). LCMS: P=97%, retention time=0.9 min, (M+H)⁺: 222.

Synthesis of8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine3g

Step 1: Synthesis of tert-butyl8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate3.1g

Iminoether 1b (468 mg, 1.93 mmol, 1 eq.) was dissolved in anhydrous EtOH(2 mL), to which was added carbohydrazide 2r (270 mg, 1.79 mmol, 1 eq.).The resulting mixture was stirred at 135° C. in oil bath for 63 h. Thereaction mixture was allowed to reach RT whereupon volatiles wereremoved under reduced pressure. The crude compound was then purifiedusing silica gel chromatography (DCM/MeOH: 99/1 to 98/2) to afford thedesired product 3.1g as yellow oil (380 mg, 1.15 mmol, 65%). LCMS:P=95%, retention time=2.2 min, (M+H)⁺: 330.

Step 2: Synthesis of8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine3g dihydrochloride salt

4M HCl in dioxane (5.77 mL, 23.07 mmol) was added to a solution of 3.1g(380 mg, 1.15 mmol) in iso-propanol (10 mL). The reaction mixture wasstirred at 60° C. for 1 h. The reaction mixture was allowed reach RT andthen further cooled to 0° C. The precipitate eventually obtained wasfiltered and dried in vacuo to afford 3g as yellow solid. (367 mg,quant.). LCMS: P=92%, retention time=0.2 min, (M+H)⁺: 230.

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method D:

intermediate 3 h:6-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-olhydrochloride salt, from intermediates 1c and 2s;

intermediate 3i:3-(6-bromopyridin-2-yl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinedihydrochloride salt, from intermediates 1b and 2t.

Method E: Cyclodehydration and Acydolysis—DMB Protection

Method E is the procedure used for the synthesis of thetriazolopiperazine 3 and is detailed below:

Method E is illustrated by the synthesis of intermediates 3j and 3qwherein the protecting group is DMB.

Synthesis of2-ethyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3j

Step 1: Synthesis of4-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-ethylthiazole3.1j

In a 10 mL round-bottom flask equipped with a condenser, imino-ether 1c(790 mg, 2.70 mmol, 1 eq.) was dissolved in anhydrous EtOH (2.5 mL), towhich was added 2-methylthiazole-4-carbohydrazide 2c (462 mg, 2.70 mmol,1 eq.) in one portion. The resulting solution was stirred at 135° C.overnight. Thereafter, the reaction mixture was brought to RT and thevolatiles removed under reduced pressure. The crude compound was thenpurified using silica gel chromatography (DCM/MeOH: 99/1 to 98/2) toafford the desired product 3.1j as yellow solid (837 mg, 2.10 mmol,78%). LCMS: P=97%, retention time=1.9 min, (M+H)⁺: 400.

Step 2 Synthesis of2-ethyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3j

In a round-bottom flask containing 10 ml DCM was added4-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-ethylthiazole3.1j (0.837 g, 2.10 mmol). Then, TFA (10.48 mL, 141 mmol), was added tothe reaction mixture at RT. After 30 min stirring, the mixture wasconcentrated. Then ca 25 mL DCM was added to the residue thus obtained,and washed with saturated NaHCO₃ (15 mL). The aqueous layer wasextracted twice with 25 mL of DCM, the organic layers were washed with25 mL of brine, dried over MgSO₄, filtered and concentrated underreduced pressure to obtain crude 3e as a pink oil (500 mg, 96%). Thecrude 3j was directly used in the next step without furtherpurification.

In one embodiment, alternative work-up equally used involved treatmentof the dried residue obtained above with 4 M HCl/dioxane (20 eq.) at RTunder stirring. After 5 min, Et₂O was added to help precipitation. Thisprecipitate was filtered off under vacuum, washed with Et₂O and driedunder high vacuum to furnish 3j.

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method E:

intermediate 3k:4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-vinylthiazolefrom intermediates 1c and 2d; the Boc aminoethyl derivative 3.1kisolated after condensation was first Boc-deprotected (8 eq ofHCl/dioxane). Following dimethylamine elimination (using 10 eq of NaHand MeI at RT), the vinyl moiety obtained was then DMB-deprotected as instep 2 above to furnish 3k;intermediate 3l:2-methyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole,from intermediates 1c and 2e;intermediate 3m2-isopropyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole,from intermediates 1c and 2f;intermediate 3n:2-cyclopropyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole,from intermediates 1c and 2g;intermediate 3o:2,5-dimethyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,from intermediates 1c and 2 h;intermediate 3p:4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-amine,from intermediates 1c and 2g.

Synthesis of4,5-dimethyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazolehydrochloride 3q

Step 1: Synthesis of2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4,5-dimethylthiazole3.1q

Iminoether 1d (768 mg, 2.63 mmol, 1 eq.) was dissolved in anhydrous EtOH(5 mL), to which was added 4,5-dimethylthiazole-2-carbohydrazide 2l (450mg, 2.63 mmol, 1 eq.) and the resultant reaction mixture was refluxedfor 48 hours. The reaction mixture was then brought to RT and thevolatiles was removed under reduced pressure, whereupon the isolatedcrude was purified using silica gel chromatography (DCM/MeOH: 100/0 to98/2) to afford the desired product 3.1q (786 mg, 1.93 mmol, 74%). LCMS:P=65%, retention time=1.9 min, (M+H)⁺: 400.

Step 2: Synthesis of4,5-dimethyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3c

To 3.1q (0.786 g, 1.97 mmol) in anhydrous DCM (6.6 mL) at RT was addedTFA (9.1 mL, 148 mmol) and the mixture refluxed for 30 min whereupon thevolatiles were removed under vacuum. 4M HCl in dioxane (5 mL, 20 mmol)was added dropwise at RT with stirring. After 5 min, Et₂O was added tohelp precipitation of the product, whereupon it was filtered, washedwith Et₂O and dried under vacuum to afford 3q (729 mg, 100%). LCMS:P=100%, retention time=1.6 min, (M+H)⁺: 250.

In one embodiment 20 eq. of TFA at RT in DCM (1:1 mixture DCM/TFA v/v)was used to carry out this reaction.

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method E:

intermediate 3r:3-methyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazolehydrochloride, from intermediates 1c and 2m;

intermediate 3s:3-methyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazolehydrochloride, from intermediates 1c and 2n;

intermediate 3t:4-methyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazolehydrochloride, from intermediates 1c and 2o;

intermediate 3u:3-isopropyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazolehydrochloride, from intermediates 1c and 2p.

Method F: Cyclodehydration and Acydolysis—PMB Protection

Method F is the procedure used for the synthesis of thetriazolopiperazine 3 and is detailed below:

Method F is illustrated by the synthesis of intermediate 3v wherein theprotecting group is PMB.

Synthesis of4-methyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3v

Step 1: Synthesis of2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-methylthiazole3.1v

Imino-ether 1d (444 mg, 1.69 mmol, 1 eq.) was dissolved in anhydrousEtOH (5 mL), to which was added 2-methylthiazole-4-carbohydrazide 2k(266 mg, 1.69 mmol, 1 eq.) and the resultant solution was refluxed for24 h. The reaction mixture was cooled to RT and the solvent was removedunder reduced pressure. The crude compound was then purified on silicagel (DCM/MeOH: 99/1 to 98/2) to afford the desired product 3.1v as apale yellow solid (383 mg, 1.07 mmol, 64%). LCMS: P=75%, retentiontime=1.9 min, (M+H)⁺: 356.

Step 2: Synthesis of4-methyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3v

Anhydrous DCM (2.5 mL) was added at RT to2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-methylthiazole3.1v (443 mg, 1.246 mmol, 1 eq.). TFA (2.5 mL, 33.5 mmol, 27 eq.) wasthen added and the reaction mixture refluxed for 15 h. The reaction wasquenched by addition of NaHCO₃ sat. solution. The layers were separatedand the aqueous layer was basified to pH˜14 with NaOH 1M solution andwas extracted with DCM (3×70 mL). Combined organic layers were washedwith brine (˜70 mL), dried over MgSO4, filtered and concentrated underreduced pressure to afford 3v after vacuum during for 3 h without massvariation. (342 mg, 100%). LCMS: P=100%, retention time=1.2 min, (M+H)⁺:236.

The following intermediate was also prepared from the ad hoc reagentsand intermediates using General Method F:

Intermediate 3w:3-(1,3-dimethyl-1H-pyrazol-5-yl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine,from intermediates 1d and 2q.

I.5. Step 4: Acylation Leading to Final Products

Method G: Acylation and Chiral HPLC Purification

Method G is the procedure used for the synthesis of the racemic product4 and its purification to obtain final compounds no. X of generalFormula I. Method G is detailed below:

Method G is illustrated by the synthesis of compounds no. 5, 19, 29 and33 of general Formula I.

Synthesis of(3-(2-ethylthiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone4a and(R)-(3-(2-ethylthiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanoneCompound No. 5

To a solution of crude 3j (250 mg, 1.003 mmol, 1 eq.) in anhydrous DCM(10 mL) were added, at RT, 4-(thiophen-2-yl)benzoyl chloride 4.1a (290mg, 1.303 mmol, 1.3 eq.), followed by N-methylmorpholine (0.359 mL, 3.51mmol, 3.5 eq.) dropwise over 15 sec. The reaction mixture was stirred atRT for 10 minutes and the milky suspension was poured into 10 mL of 1 MHCl solution. The aqueous phase was extracted with DCM (3×10 mL). Theorganic phases were combined, washed with 1 M NaOH (20 mL), brine (20mL), dried over MgSO₄ and evaporated to dryness. The residue wassolubilized in DCM (4 mL) and Et₂O was slowly added (5 mL) to induceprecipitation. The solid was filtered off, washed with 2 mL of Et₂O anddried under vacuum to afford 4a as yellow powder (234 mg, 0.537 mmol,54%). LCMS: P=97%, retention time=2.4 min, (M+H)⁺: 436.

4a was purified by chiral preparative HPLC according to theabovementioned method to yield title compound no. 5 as a white powder.LCMS: P=100%, retention time=4.3 min, (M+H)⁺: 436; Chiral HPLC retentiontime: 14.0 min; ee>99%; ¹H-NMR (CDCl₃): δ 8.02 (s, 1H), 7.70 (d, J=8.2,2H), 7.47 (d, J=8.2, 2H), 7.31 (m, 2H), 7.12 (m, 1H), 5.77 (br, 1H),4.83 (m, 1H), 4.63 (br, 1H), 4.26 (m, 1H), 3.53 (m, 1H), 3.07 (d,0.1=7.5, 2H), 1.74 (d, 0.1=6.9, 3H), 1.43 (t, 0.1=7.5, 3H).

Synthesis of(8-methyl-3-(4-methylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone4b and(R)-(8-methyl-3-(4-methylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanoneCompound No. 19

To a solution of 3v (342 mg, 1.25 mmol, 1 eq.) in commercial anhydrousDCM (12 mL) at RT were added 4-(thiophen-2-yl)benzoyl chloride 4.1a (326mg, 1.464 mmol, 1.17 eq.), followed by N-methylmorpholine (0.128 mL,1.25 mmol, 1.0 eq.) dropwise over 15 sec. The reaction mixture wasstirred at RT for 15 minutes and then diluted with DCM (60 mL). Theorganic layer was washed with water (40 mL), brine (50 mL), dried overMgSO₄, filtered and evaporated under reduced pressure. The residue waspurified on silica gel (DCM/MeOH: 98/2) to afford 4b as yellow oil with88% purity by LCMS. Diethylether (10 mL) was added on obtained oil andmixture was sonicated. A white solid precipitated and was filtered. Thefiltrate was concentrated under reduced pressure and diethylether (5 mL)was added on the residue. After sonication, a second white precipitatewas filtered. Both precipitates were merged to afford 4b as white solid(189 mg, 36%). LCMS: P=99%, retention time=4.4 min, (M+H)⁺: 422.

4b was purified by chiral preparative HPLC according to theabovementioned method to yield title compound no. 19 as white powder.LCMS: P=100%, retention time=4.3 min, (M+H)⁺: 422; Chiral HPLC retentiontime: 6.6 min, ee=94%; ¹H-NMR (CDCl₃): δ 7.70 (d, J=8.2, 2H), 7.48 (d,J=8.2, 2H), 7.40-7.35 (m, 2H), 7.13-7.11 (m, 1H), 7.00 (m, 1H), 5.81(br, 1H), 4.95 (dd, J₁=3.3, J₂=14.0, 1H), 4.60 (br, 1H), 4.27 (td,J₁=3.9, J₂=12.7, 1H), 3.51 (m, 1H), 2.50 (s, 3H), 1.75 (d, _(J)=6.9,3H).

When hydrochloride salt of 3 was used, 2.2 eq. of N-methylmorpholinewere added.

Synthesis of Compound No. 29:(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone

To a solution of 3g (500 mg, 1.65 mmol, 1 eq.) in anhydrous DCM (10 mL)were added at RT [1,1′-biphenyl]-4-carbonyl chloride 4.1c (430 mg, 1.98mmol, 1.2 eq.), followed by N-methylmorpholine (507 μL, 4.96 mmol, 3.00eq.). The reaction mixture was stirred at RT for 30 min. whereuponsaturated NaHCO₃ solution (10 mL) and DCM (5 mL) were added to thereaction mixture. The organic phase was extracted, dried over MgSO₄,filtered and concentrated under reduced pressure. The crude product waspurified using silica gel chromatography (eluent: DCM/MeOH: 98:2) toafford 268 mg of 4c. LCMS: P=98%, retention time=4.2 min, (M+H)⁺: 410.

4c was purified by chiral preparative HPLC according to theabovementioned method to yield title compound no. 29 as a white powder.LCMS: P=100%, retention time=4.2 min, (M+H)⁺: 410; Chiral HPLC retentiontime: 4.7 min; ee>99%. ¹H-NMR (CDCl₃): δ 8.11 (d, J=7.7, 1H), 7.67-7.40(m, 10H), 7.20 (d, J=6.7, 1H), 5.78 (bs, 1H), 5.00 (dd, J₁=3.3, J₂=14.0,1H), 4.67 (br, 1H), 4.37 (m, 1H), 3.51 (m, 1H), 2.58 (s, 3H), 1.76 (d,J=6.9, 3H).

The procedure used for the synthesis of compound no. 33 is thefollowing:

Step 1: Synthesis of(3-(6-bromopyridin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 4d 4d was prepared from 3iand 4.1a according to General Method G Step 2: Synthesis of6-(8-methyl-7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)picolinonitrile4e

A mixture of 4d (140 mg, 0.291 mmol) and zinc cyanide (137 mg, 1.166mmol) in DMA (2 mL) at RT was degassed. Then Pd(PPh₃)₄(67.4 mg, 0.058mmol) was added (67.4 mg, 0.058 mmol). The reaction mixture was stirredat 115° C. for 30 min. whereupon DCM (30 mL) was added and the organiclayer extract was washed with water (2×30 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified using silica gel chromatography (DCM/MeOH: 100/0 to 98/2) toafford 4d as white solid (8 mg, 6%). LCMS: P=90%, rt=4.2 min, (M+H)⁺:427.

4d was purified by chiral preparative HPLC according to theabovementioned method to yield title compound no. 33 as white powder.LCMS: P=100%, retention time=4.2 min, (M+H)⁺: 427; Chiral HPLC retentiontime: 18.8 min; ee=98%.

II. Chiral Synthesis II.1. General Synthetic Scheme for Chiral Synthesis

Compounds of the invention were synthesized using the chiral process ofthe invention described in Scheme 30.

Chiral ketopiperazine A was protected with a DMB group and converted toiminoether D by using the Meerwein reagent (Et₃OBF₄). Condensationreaction between the acyl hydrazide E and iminoether D was conductedunder heating conditions in ethanol to provide DMB protected piperazineF that was subsequently deprotected with HCl in dioxane to yieldcompound of Formula II.

In one embodiment, the DMB deprotection step (from F to II) was carriedout using TFA in DCM.

In one embodiment, the DMB group deprotection step (from F to II) iscarried out using TFA in DCM at RT, followed by either TFA salt exchangewith HCl or extraction at high pH recovering free piperazine II.

Acylation with the appropriate acid chloride afforded the final productof Formula I typically in >90% enantiomeric excess (chiral HPLC).

General Method H

General Method A is the procedure used for the synthesis of(R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one (R)—C (cf. Scheme30).

In a round-bottom flask, were sequentially introduced(R)-3-methylpiperazin-2-one (R)-A (725 mg, 6.35 mmol, 1 eq.),2,4-dimethoxybenzaldehydeB (1.16 g, 6.99 mmol, 1.1 eq.), acetic acid(545 μl, 9.53 mmol, 1.5 eq.) and sodium triacetoxyborohydride (1.88 g,8.89 mmol, 1.4 eq.) in commercial anhydrous acetonitrile (65 mL), at RT,under N₂ atmosphere. The reaction was stirred at RT overnight. Thereaction mixture was quenched carefully at 0° C. with saturated NaHCO₃solution (100 mL) until no more bubbling was observed. Aqueous andorganic layers were separated. The aqueous layer was extracted withEtOAc (3×100 mL) and the combined organic layers were washed with brine,dried over MgSO₄′ filtered, and concentrated under reduced pressure toafford the title compound as yellow oil. The crude compound was thenpurified on silica gel (DCM/MeOH: 98/2 to 95/5) to afford the desiredproduct (R)—C as a viscous pale yellow oil. Yield: 1.65 g, 98%. LCMS:P=100%, retention time=1.6 min, (M+H)⁺: 265; chiral HPLC retentiontime=41.5 min, ee>99%; ¹H-NMR (CDCl₃): δ 7.23 (d, J=8.9, 1H), 6.49 (d,J=8.9, 1H), 6.46 (s, 1H), 6.29 (br, 1H), 3.81 (s, 3H), 3.80 (s, 3H),3.78 (d, J_(AB)=15.0, 1H), 3.49 (d, J_(AB)=15.0, 1H), 3.27 (m, 2H), 3.19(m, 1H), 2.95 (m, 1H), 2.48 (m, 1H), 1.48 (d, J=6.8, 3H).

The (S)-4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one (S)—C was alsoprepared using General Method H starting from(S)-3-methylpiperazin-2-one (S)-A. Yield: 300 mg, 99%. LCMS: P=100%,retention time=1.6 min, (M+H)⁺: 265; chiral HPLC retention time=26.6min, ee>99%.

General Method I:

General Method I is the procedure used for the synthesis of(R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine(R)-D (cf. Scheme 30) as detailed below.

Oven dried (115° C.) sodium carbonate (2.48 g, 23.40 mmol, 2.25 eq.) wasplaced in a round-bottom flask. The round-bottom flask was backfilledwith Ar and then capped with a rubber septum. A solution of(R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one (R)—C (2.75 g, 10.40mmol, 1 eq.) in anhydrous DCM (35 mL) was added, followed by freshlyprepared triethyloxonium tetrafluoroborate (2.48 g, 13.05 mmol, 1.25eq.) in one portion. Thereafter the reaction mixture was stirred furtherat RT for 1 hour, whereupon the reaction mixture was diluted withsaturated aqueous NaHCO₃ (100 mL). The aqueous layer was extracted withDCM (3×200 mL). The organic layers were combined, dried over MgSO₄,filtered and concentrated under reduced pressure to afford 3.1 g ofyellow oil. The crude compound was then purified on silica gel(EtOAc/MeOH: 99/1) to afford the desired product (R)-D as a pale yellowoil. Yield: 1.44 g, 48%. LCMS: P=95%, retention time=1.8 min,(M+H2O+H)⁺: 311; chiral HPLC retention time=12.3 min, ee>97%. ¹H-NMR(CDCl₃): δ 7.23 (d, J=8.8, 1H), 6.48 (d, J=8.8, 1H), 6.44 (s, 1H), 4.02(m, 2H), 3.92 (s, 6H), 3.86 (d, J_(AB)=14.0, 1H), 3.46 (d, J_(AB)=14.0,1H), 3.44 (m, 2H), 3.10 (m, 1H), 2.79 (m, 1H), 2.32 (m, 1H), 1.35 (d,J=6.8, 3H), 1.24 (t, J=6.0, 3H).

The(S)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine(S)-Dwas also prepared using General Method I starting from (S)—C (46 mg,0.16 mmol, 59%). LCMS: P=100%, retention time=1.8 min, (M+H2O+H)⁺: 311;chiral HPLC retention time=11.3 min, ee=96%.

General Method J:

General Method J is the procedure used for the synthesis of hydrazideE.a (cf scheme 31) as detailed below.

Synthesis of 2-methylthiazole-4-carbohydrazide E.a

In a 100 mL round-bottom flask equipped with a condenser, ethyl2-methylthiazole-4-carboxylate E.1a (10 g, 58.4 mmol, 1 eq.) wasdissolved in anhydrous EtOH (25 mL) and treated at RT with hydrazinemonohydrate (17.0 mL, 354.4 mmol, 6 eq.). The resulting yellow solutionwas heated at reflux temperature for 14 h. After allowing the reactionmixture to come to RT, the solution was concentrated under reducedpressure to afford 13.4 g of a brown oil. Co-evaporations using 3×200 mLof a mixture of commercial anhydrous DCM:MeOH (1:1) were performed toremove residual water. The residue was then recrystallized from hot EtOH(60 mL): after total dissolution, the mixture was then allowed to cooldown to RT and then put at 0° C. (with an ice bath) for 40 min. Theobtained crystals were filtered and washed with cooled (0° C.) EtOH(2×30 mL). The orange solid was dried under vacuum for 1 h to afford E.a(5.85 g, 37.2 mmol, 64%). LCMS: P=100%, retention time=0.5 min, (M+H)⁺:158; ¹H-NMR (CDCl₃): δ 8.32 (br, 1H), 7.96 (s, 1H), 4.07 (br, 2H), 2.70(s, 3H).

General Method K:

General Method K is the general procedure used for the synthesis ofchiral triazolopiperazine intermediates F (cf. scheme 30) and isdetailed below in scheme 32 with the synthesis of(R)-4-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-methylthiazole(R)-F.a.

In a 50 mL round-bottom flask equipped with a condenser, imino-ether(R)-D (4.51 g, 14.96 mmol, 1 eq.) was dissolved in anhydrous EtOH (15mL), to which was added 2-methylthiazole-4-carbohydrazide E.a (2.35 g,14.96 mmol, 1 eq.) in one portion. The resulting solution was stirred at70° C. for 6 hours. The reaction mixture was cooled down to RT and thesolvent was removed under reduced pressure. The crude compound was thenpurified by silica gel chromatography (DCM/MeOH: 99/1 to 95/5) to affordthe desired product (R)-F.a as pale yellow foamy solid. Yield: 3.78 g,65%. LCMS: P=96%, retention time=1.8 min, (M+H)⁺: 386; chiral HPLCretention time=13.9 min, ee=95%; ¹H-NMR (CDCl₃): δ 7.85 (s, 1H), 7.19(s, 1H), 6.41 (m, 2H), 4.38 (m, 1H), 4.16 (m, 1H), 3.96 (m, 1H), 3.86(d, J_(AB)=15.0, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.56 (d, J_(AB)=15.0,1H), 3.11 (m, 1H), 2.66 (s, 3H), 2.62 (m, 1H), 1.64 (d, J=6.6, 3H);¹³C-NMR (CDCl₃): δ 166.2, 160.2, 158.8, 154.6, 148.1, 143.1, 130.9,118.8, 118.2, 104.2, 98.5, 77.6, 77.2, 76.8, 70.4, 70.2, 55.4, 55.4,55.8, 50.2, 45.8, 44.2, 19.2, 17.7, 15.7.

In a round-bottom flask equipped with a condenser, imino-ether (R)-D(890 mg, 3.04 mmol, 1 eq.) was dissolved in anhydrous EtOH (3 mL), towhich was added 2-methylthiazole-4-carbohydrazide E.a (479 mg, 3.04mmol, 1 eq.). The resulting solution was stirred at 70° C. for 7 hours,then brought to RT and the volatiles removed under reduced pressure. Thecrude compound was then purified by silica gel chromatography (DCM/MeOH:99/1 to 95/5) to afford the desired product F.a as pale yellow oil.Yield: 685 mg, 58%. LCMS: P=96%, retention time=1.8 min, (M+H)⁺: 386;chiral HPLC retention time: 14.3 min, ee=95%; ¹H-NMR (CDCl₃): δ 7.85 (s,1H), 7.19 (s, 1H), 6.41 (m, 2H), 4.38 (m, 1H), 4.16 (m, 1H), 3.96 (m,1H), 3.86 (d, J_(AB)=15.0, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.56 (d,J_(AB)=15.0, 1H), 3.11 (m, 1H), 2.66 (s, 3H), 2.62 (m, 1H), 1.64 (d,J=6.6, 3H).

The(S)-4-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-methylthiazole(S)-F.awas also prepared using General Method K starting from (S)-D (36 mg,0.09 mmol, 54%). LCMS: P=90%, retention time=1.8 min, (M+H)⁺: 386;chiral HPLC retention time=21.0 min, ee=94.0%.

General Method L:

General Method E is the general procedure used for the synthesis ofcompounds of Formula II salts (cf. compounds II in scheme 30) and isdetailed below in scheme 33 with the synthesis of compound no. II-1:(R)-8-methyl-3-(2-methylthiazol-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-7-iumchloride(R)-II-1.

In a 50 mL round-bottom flask equipped with a condenser, were introduced(R)-F.a (262 mg, 0.68 mmol, 1 eq.) followed by a solution of HCl 4 M indioxane (3.4 mL, 13.60 mmol, 20 eq.) in one portion. The resultingyellow solution was stirred at 100° C. After 6 hours, i-PrOH (6 mL) wasadded to the hot reaction mixture. The solution was then allowed toreach RT by removing the oil bath. Et₂O (15 mL) was then added and theobtained precipitate was filtered off, washed with Et₂O (3 mL) andair-dried overnight to afford (R)-II-1 (235 mg, 0.86 mmol, 100%) as apink solid which was used in the next step without further purification.

The(S)-2-methyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole(S)-II-1was prepared using TFA procedure, starting from (S)-F.a as followed:

(S)-F.a (36 mg, 0.09 mmol, 1 eq.) was dissolved in dry DCM (500 μL). TFA(467 μL, 6.0 mmol, 65 eq.) was added dropwise at RT. After 30 minutes,the dark pink reaction mixture was quenched carefully with a saturatedsolution of NaHCO₃ (10 mL). The aqueous phase was extracted with DCM(3×10 mL). Organic phases were combined, washed with brine (10 mL),dried over MgSO4, filtered and concentrated under reduced pressure toafford the free amine (S)-II-1 as white solid (43 mg, 0.183 mmol, 100%)which was used in the next step without further purification.Determination of Enantiomeric Excess:

As aforementioned, given that chiral LC determination of % ee proveddifficult for compounds of Formula II, specifically due to technicalchiral LC issues in dealing with such amines, the % ee was determinedthrough the product formed at the subsequent step wherein the amine wasacylated to furnish the final products exemplified through but notlimited to compound no. 1 of Formula I.

General Method M:

General Method M is the general procedure used for the synthesis ofchiral triazolopiperazine compounds of the invention and is detailedbelow with the synthesis of(R)-(8-methyl-3-(2-methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone(R)-compound no. 1 of Formula I (hereunder noted I-1).

To a solution of crude (R)-II-1 (235 mg, 0.67 mmol, 1 eq.) in anhydrousDCM (10 mL) were added at 0° C. 4-(thiophen-2-yl)benzoyl chloride 4.1a(165 mg, 0.742 mmol, 1.3 eq.), followed by N-methylmorpholine (163 μL,1.48 mmol, 2.2 eq.) dropwise over 15 sec. The reaction mixture wasstirred at RT for 10 minutes and, the milky suspension was poured into10 mL of 1 M HCl. The aqueous phase was extracted with DCM (3×10 mL).The organic phases were combined, washed with 1 M NaOH (20 mL), brine(20 mL), dried over MgSO₄ and evaporated to dryness. The crude compoundwas purified by silica gel chromatography (eluent: EtOAc/MeOH: 98/2) toafford the desired product (R)—I-1 as a white foam. Yield: 158 mg, 55%.LCMS: P=97%, retention time=4.0 min, (M+H)⁺: 422; Chiral HPLC retentiontime=15.4 min, ee=95%; ¹H-NMR (CDCl₃): δ 7.93 (s, 1H), 7.61 (d, J=7.9,2H), 7.40 (d, J=7.9, 2H), 7.31 (m, 2H), 7.04 (m, 1H), 5.73 (m, 1H), 4.78(m, 1H), 4.46 (m, 1H), 4.14 (m, 1H), 3.47 (m, 1H), 2.70 (s, 3H), 1.68(d, J=6.7, 3H). ¹³C-NMR (CDCl3): δ 170.3, 166.5, 151.9, 148.0, 142.4,136.4, 128.1, 125.8, 124.0, 119.3, 77.4, 77.0, 76.6, 44.8, 30.7, 19.6,19.1.

Identical % ee was obtained for compounds (R)—I-1 and (R)-F.a thusconfirming that no detectable racemization occurs during the acidolyticdeprotection and N-acylation steps.

Compound(S)-(8-methyl-3-(2-methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone(S)—I-1 was also prepared using General Method F starting from(S)-II-1(16 mg, 38.0 μmol, 40%). LCMS: P=90%, retention time=4.0 min,(M+H)⁺: 386.1; chiral HPLC retention time=11.0 min, ee=92%.

X-ray Crystallographic Characterization of Compound (R)—I-1.

Compound(R)—I-1 was characterized by single crystal X-ray spectroscopythus establishing the configuration of the more active enantiomer asbeing the (R)-configuration (see FIG. 1).

Method.

All data were recorded on a MAR345 image plate (MARRESEARCH) using MoKαradiation (λ=0.71073). X-rays were generated on a RIGAKU rotating anodegenerator with power settings of 50 KV and 70 mA. A Zr filter is used toeliminate the MoKα radiation. A suitable crystal was chosen under amicroscope, mounted in a nylon loop and aligned on the goniometer priorto the x-ray experiment. A total of 174 images corresponding to a 2.0°phi rotation were collected at room temperature. The reflections on thediffraction images were indexed and integrated using the Automar dataprocessing suite (MARRESEARCH). During the integration the friedel pairswere kept unmerged in order to preserve the anomalous signal needed forabsolute structure determination. Xprep (Bruker) was used to determinethe spacegroup and to generate the reflection and instruction files forstructure determination and subsequent refinement. Structure solutionwas performed by SHELXS and the refinement was done by SHELXL (“A shorthistory of SHELX”. Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122).The free rotation around the C6-C1 (C1A or C1B) results in rotationalisomerism in a 58/42% ratio as seen in FIG. 1 below. As depicted in theX-ray Figure below the chirality of C22 carbon atom is established as R.(H. D. Flack (1983). “On Enantiomorph-Polarity Estimation”. Acta CrystA39: 876-881; J. Appl. Cryst. (2008), 41, 96-103.)

X-ray Crystallographic Characterization of Compound (S)—I-1.

Compound(S)—I-1 was characterized by single crystal X-ray spectroscopythus establishing the configuration of the more active enantiomer asbeing the (R)-configuration (see FIG. 2).

Method.

All data were recorded on a MAR345 image plate (MARRESEARCH) using MoKαradiation (λ=0.71073). X-rays were generated on a RIGAKU rotating anodegenerator with power settings of 50 KV and 70 mA. A Zr filter is used toeliminate the MoKα radiation. A suitable crystal was chosen under amicroscope, mounted in a nylon loop and aligned on the goniometer priorto the x-ray experiment. A total of 174 images corresponding to a 2.50phi rotation were collected at room temperature. The reflections on thediffraction images were indexed and integrated using the Automar dataprocessing suite (MARRESEARCH). During the integration the friedel pairswere kept unmerged in order to preserve the anomalous signal needed forabsolute structure determination. Xprep (Bruker) was used to determinethe spacegroup and to generate the reflection and instruction files forstructure determination and subsequent refinement. Structure solutionwas performed by SHELXS and the refinement was done by SHELXL (“A shorthistory of SHELX”. Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122).The free rotation around the C6-C1 (C1A or C1B) results in rotationalisomerism in a 58/42% ratio as seen in FIG. 1 below. As depicted in theX-ray Figure below the chirality of C22 carbon atom is established as R.(H. D. Flack (1983). “On Enantiomorph-Polarity Estimation”. Acta CrystA39: 876-881; J. Appl. Cryst. (2008), 41, 96-103.)

It can be readily appreciated that related compounds of the inventionmay be synthesized from the ad hoc reagents using the general methodsand procedures described herein.

III. X-Ray Crystallographic Characterization III.1. Compound No. 1

Compound no. 1 was characterized by single crystal X-ray spectroscopythus establishing the configuration of the more active enantiomer as the(R)-configuration (see FIG. 1).

Methods.

All data were recorded on a MAR345 image plate (MARRESEARCH) using MoKαradiation (λ=0.71073). X-rays were generated on a RIGAKU rotating anodegenerator with power settings of 50 KV and 70 mA. A Zr filter is used toeliminate the MoKα radiation. A suitable crystal was chosen under amicroscope, mounted in a nylon loop and aligned on the goniometer priorto the x-ray experiment. A total of 174 images corresponding to a 2.0°phi rotation were collected at room temperature. The reflections on thediffraction images were indexed and integrated using the Automar dataprocessing suite (MARRESEARCH). During the integration the friedel pairswere kept unmerged in order to preserve the anomalous signal needed forabsolute structure determination. Xprep (Bruker) was used to determinethe spacegroup and to generate the reflection and instruction files forstructure determination and subsequent refinement. Structure solutionwas performed by SHELXS and the refinement was done by SHELXL (“A shorthistory of SHELX”. Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122).The free rotation around the C6-C1 (C1A or C1B) results in rotationalisomerism in a 58/42% ratio as seen in FIG. 1 below. As depicted in theX-ray FIG. 1 the chirality of C22 carbon atom is established as R. (H.D. Flack (1983). “On Enantiomorph-Polarity Estimation”. Acta Cryst A39:876-881; J. Appl. Cryst. (2008), 41, 96-103.)

III.2. Compound No. 19

Compound no. 19 in the present invention was characterized by singlecrystal X-ray spectroscopy that established the configuration of themore active enantiomer as (R) (see FIG. 2).

Methods.

All data were recorded on a MAR345 image plate (MARRESEARCH) using MoKαradiation (λ=0.71073). X-rays were generated on a RIGAKU rotating anodegenerator with power settings of 50 KV and 70 mA. A Zr filter is used toeliminate the MoKα radiation. A suitable crystal was chosen under amicroscope, mounted in a nylon loop and aligned on the goniometer priorto the x-ray experiment. A total of 103 images corresponding to a 1.5°phi rotation were collected at room temperature. The reflections on thediffraction images were indexed and integrated using the Automar dataprocessing suite (MARRESEARCH). During the integration the friedel pairswere kept unmerged in order to preserve the anomalous signal needed forabsolute structure determination. Xprep (Bruker) was used to determinethe spacegroup and to generate the reflection and instruction files forstructure determination and subsequent refinement. Structure solutionwas performed by SHELXS and the refinement was done by SHELXL (“A shorthistory of SHELX”. Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122).The free rotation around the C6-C1 (CIA or C1B) results in rotationalisomerism in a 56/44% ratio as seen in FIG. 2 below. As depicted in theX-ray FIG. 2 the chirality of C22 carbon atom is established as R. (H.D. Flack (1983). “On Enantiomorph-Polarity Estimation”. Acta Cryst A39:876-881; J. Appl. Cryst. (2008), 41, 96-103.)

IV. Summary of Methods and Reagents Used for the Synthesis of theCompounds of the Invention

Compounds of the invention of general Formula I were synthesized fromthe ad hoc reagents and intermediates using the general methods andprocedures described above. Table 4 hereunder recapitulates theintermediates and general methods used for each compound as well as LCMSanalytical data.

TABLE 4 Chiral Chiral HPLC HPLC LCMS Retention Retention Chiral TriazoloLCMS Retention time(S- time (R- HPLC ee Cpd piperazine Acyl chlorideGeneral Purity time LCMS enantiomer) enantiomer) Method (R) nointermediate intermediate method (%) (min) [M + H]⁺ (min) (min) name (%)1 II-1 4-(thiophen-2- General 97 3.97 422 11.1 15.3 A 95.3 yl)benzoylMethod M chloride 2 II-1 [1,1′-biphenyl]-4- General 97 4.07 416 10.914.1 A 93.0 carbonyl chloride Method M 3 3a 4-(thiophen-2- General 953.97 408 — — — — yl)benzoyl Method G chloride 4 3b 4-(thiophen-2-General 97 4.44 462 — — — — yl)benzoyl Method G chloride 5 3j 4-(thiophen-2- General 100 4.31 436 10.0 14.0 A 99.5 yl)benzoyl Method Gchloride 6 3j  [1,1′-biphenyl]-4- General 99 4.34 430 6.5 10.4 B 99.5carbonyl chloride Method G 7 3k 4-(thiophen-2- General 100 4.28 434 10.015.0 A 99.6 yl)benzoyl Method G chloride 8 3k [1,1′-biphenyl]-4- General100 4.36 428 9.9 14.3 A 99.0 carbonyl chloride Method G 9 3c4-(thiophen-2- General 95 4.13 420 — — — — yl)benzoyl Method G chloride10 3c [1,1′-biphenyl]-4- General 95 4.22 414 — — — — carbonyl chlorideMethod G 11 3l  4-(thiophen-2- General 100 3.74 406 10.6 15.2 A 96.0yl)benzoyl Method G chloride 12 3l  [1,1′-biphenyl]-4- General 99 3.87400 10.1 13.6 A 99.4 carbonyl chloride Method G 13  3m 4-(thiophen-2-General 98 4.32 434 9.2 13.5 A 99.9 yl)benzoyl Method G chloride 14 3d4-(thiophen-2- General 94 4.17 420 — — — — yl)benzoyl Method G chloride15 3n 4-(thiophen-2- General 96 4.14 432 7.0 9.7 B 99.9 yl)benzoylMethod G chloride 16 3o 4-(thiophen-2- General 100 4.13 436 8.2 10.9 A64   yl)benzoyl Method G chloride 17 3p 4-(thiophen-2- General 98 4.03451 18.1 14.2 C 96.0 yl)benzoyl Method G chloride furnishedaminothiazole 4that was then dimethylated using conventional method 183e 4-(thiophen-2- General 92 4.36 436 — — — — yl)benzoyl Method Gchloride 19 3v 4-(thiophen-2- General 100 4.30 422 5.9 6.6 A 94.0yl)benzoyl Method G chloride 20 3v [1,1′-biphenyl]-4- General 99 4.41416 6.3 8.7 B 99.5 carbonyl chloride Method G 21 3f  [1,1′-biphenyl]-4-General 98 4.52 402 — — — — carbonyl22chloride Method G 22 3q4-(thiophen-2- General 99 4.52 436 6.6 8.5 B 99.0 yl)benzoyl Method Gchloride 23 3r  4-(thiophen-2- General 100 4.01 407 6.5 8.7 B 99.8yl)benzoyl Method G (3/2/0.5 chloride ratio used) 24 3s  4-(thiophen-2-General 100 4.24 423 6.34 7.73 B− 99.0 yl)benzoyl Method G chloride 253u 4-(thiophen-2- General 97 4.84 451 5.3 7.7 B− 93.0 yl)benzoyl MethodG chloride 26 3t  4-(thiophen-2- General 100 4.02 406 7.3 10.1 B− 99.6yl)benzoyl Method G chloride 27 3t  [1,1′-biphenyl]-4- General 100 4.09400 6.5 8.5 B 99.9 carbonyl chloride Method G 28  3w 4-(thiophen-2-General 100 3.85 419 7.3 9.2 B 96.0 yl)benzoyl Method G chloride 29 3g[1,1′-biphenyl]-4- General 100 4.21 410 3.5 4.7 B′ 99.9 carbonylchloride Method G 30 3g 4-(thiophen-2- General 100 4.11 416 4.6 5.4 A′99.0 yl)benzoyl Method G chloride 31 3h 4-(thiophen-2- General 100 4.48418 8.0 13.4 C′ 98.0 yl)benzoyl Method G chloride 32 3h[1,1′-biphenyl]-4- General 100 3.57 412 7.3 9.0 C′ 97.0 carbonylchloride Method G 33 3i  4-(thiophen-2- Method G 99 4.19 427 16.2 17.3C′ 98.5 yl)benzoyl chloride

In Table 4, the term “Cpd” means compound.

In Table 4 the configuration of each peak separated by chiral LC wasestablished with compound no. 1, compound no. 19 directly, and appliedto the other cases by analogy. The indirect configurational assignmentaforesaid was always confirmed through biological activity determinationthat was conclusive given the acute stereochemical SAR.

Biology Examples Functional Assay

Aequorin Assay with Human NK-3 Receptor

Changes in intracellular calcium levels are a recognized indicator of Gprotein-coupled receptor activity. The efficacy of compounds of theinvention to inhibit NKA-mediated NK-3 receptor activation was assessedby an in vitro Aequorin functional assay. Chinese Hamster Ovaryrecombinant cells expressing the human NK3 receptor and a construct thatencodes the photoprotein apoaequorin were used for this assay. In thepresence of the cofactor coelenterazine, apoaequorin emits a measurableluminescence that is proportional to the amount of intracellular(cytoplasmic) free calcium.

Antagonist Testing

The antagonist activity of compounds of the invention is measuredfollowing pre-incubation (3 minutes) of the compound with the cells,followed by addition of the reference agonist (NKA) at a finalconcentration equivalent to the EC₈₀ (3 nM) and recording of emittedlight (FDSS 6000 Hamamatsu) over the subsequent 90-second period. Theintensity of the emitted light is integrated using the reader software.Compound antagonist activity is measured based on the inhibition of theluminescence response to the addition of Neurokinin A.

Inhibition curves are obtained for compounds of the invention and theconcentrations of compounds which inhibit 50% of reference agonistresponse (IC₅₀) were determined (see results in table 5 below). The IC₅₀values shown in table 5 indicate that compounds of the invention arepotent NK-3 antagonist compounds.

TABLE 5 Compound no IC₅₀ (nM) 1 16 2 28 3 83 4 50 5 3 6 10 7 3 8 7 9 1810 20 11 34 12 58 13 2 14 47 15 9 16 30 17 7 18 10 19 8 20 11 21 33 2221 23 33 24 2 25 3 26 12 27 51 28 37 29 18 30 11 31 18Competitive Binding Assays

The affinity of compounds of the invention for the human NK-3 receptorwas determined by measuring the ability of compounds of the invention tocompetitively and reversibly displace a well-characterized NK3radioligand.

³H-SB222200 Binding Competition Assay with Human NK-3 Receptor

The ability of compounds of the invention to inhibit the binding of theNK-3 receptor selective antagonist ³H-SB222200 was assessed by an invitro radioligand binding assay. Membranes were prepared from Chinesehamster ovary recombinant cells stably expressing the human NK3receptor. The membranes were incubated with 5 nM ³H-SB222200(ARC) in aHEPES 25 mM/NaCl 0.1M/CaCl₂ 1 mM/MgCl₂ 5 Mm/BSA 0.5%/Saponin 10 μg/mlbuffer at pH 7.4 and various concentrations of compounds of theinvention. The amount of ³H-SB222200 bound to the receptor wasdetermined after filtration by the quantification of membrane associatedradioactivity using the TopCount-NXT reader (Packard). Competitioncurves were obtained for compounds of the invention and theconcentration that displaced 50% of bound radioligand (IC₅₀) weredetermined by linear regression analysis and then the apparentinhibition constant (K_(i)) values were calculated by the followingequation: K_(i)=IC₅₀/(1+[L]/K_(d)) where [L] is the concentration offree radioligand and K_(d) is its dissociation constant at the receptor,derived from saturation binding experiments (Cheng and Prusoff, 1973)(see results in table 6 below).

Table 6 shows biological results obtained using the ³H-SB222200 bindingcompetition assay with compounds of the invention. These resultsindicate that compounds of the invention display potent affinity for thehuman NK-3 receptor.

TABLE 6 Compound no Ki (nM) 1 16 2 26 3 83 4 56 5 5 6 11 7 4 8 7 9 19 1036 11 44 12 70 13 3 14 42 15 11 16 32 17 7 18 20 19 6 20 12 21 38 22 2123 29 25 3 27 51 28 68 29 23 30 10 31 22Selectivity Assay

Selectivity of the compounds of the invention was determined over theother human NK receptors, namely NK-1 and NK2 receptors.

Human NK1

The affinity of compounds of the invention for the NK1 receptor wasevaluated in CHO recombinant cells which express the human NK1 receptor.Membrane suspensions were prepared from these cells. The followingradioligand: [³H] substance P (PerkinElmer Cat#NET111520) was used inthis assay. Binding assays were performed in a 50 mM Tris/5 mM MnCl2/150mM NaCl/0.1% BSA at pH 7.4. Binding assays consisted of 25 μl ofmembrane suspension (approximately 5 μg of protein/well in a 96 wellplate), 50 μl of compound or reference ligand (Substance P) atincreasing concentrations (diluted in assay buffer) and 2 nM [³H]substance P. The plate was incubated 60 min at 25° C. in a water bathand then filtered over GF/C filters (Perkin Elmer, 6005174, presoaked in0.5% PEI for 2 h at room temperature) with a Filtration unit (PerkinElmer). The radioactivity retained on the filters was measured by usingthe TopCount-NXT reader (Packard). Competition curves were obtained forcompounds of the invention and the concentrations of compounds whichdisplaced 50% of bound radioligand (IC₅₀) were determined and thenapparent inhibition constant Ki values were calculated by the followingequation: Ki=IC₅₀/(1+[L]/K_(D)) where [L] is the concentration of freeradioligand and K_(D) is its dissociation constant at the receptor,derived from saturation binding experiments (Cheng and Prusoff, 1973).

Human NK2

The affinity of compounds of the invention for the NK2 receptor wasevaluated in CHO recombinant cells which express the human NK2 receptor.Membrane suspensions were prepared from these cells. The followingradioligand [¹²⁵I]-Neurokinin A (PerkinElmer Cat#NEX252) was used inthis assay. Binding assays were performed in a 25 mM HEPES/1 mM CaCl2/5mM MgCl2/0.5% BSA/10 μg/ml saponin, at pH 7.4. Binding assays consistedof 25 μl of membrane suspension (approximately 3.75 μg of protein/wellin a 96 well plate), 50 μl of compound or reference ligand (NeurokininA) at increasing concentrations (diluted in assay buffer) and 0.1 nM[¹²⁵I]-Neurokinin A. The plate was incubated 60 min at 25° C. in a waterbath and then filtered over GF/C filters (Perkin Elmer, 6005174,presoaked in assay buffer without saponine for 2 h at room temperature)with a Filtration unit (Perkin Elmer). The radioactivity retained on thefilters was measured by using the TopCount-NXT reader (Packard).Competition curves were obtained for compounds of the invention and theconcentrations of compounds which displaced 50% of bound radioligand(IC₅₀) were determined and then apparent inhibition constant Ki valueswere calculated by the following equation: Ki=IC₅₀/(1+[L]/K_(D)) where[L] is the concentration of free radioligand and K_(D) is itsdissociation constant at the receptor, derived from saturation bindingexperiments (Cheng and Prusoff, 1973).

The compounds of the invention, which were tested in the above NK-1 andNK-2 described assays, demonstrated a low affinity at the human NK-1 andhuman NK-2 receptors: more than 200 fold shift of the Ki compared to thehuman NK-3 receptor (table 7). Thus, compounds according to theinvention have been shown to be selective over NK1 and NK2 receptors.

TABLE 7 Compound no NK1 Ki (μM) NK2Ki (μM) NK3 Ki (nM) 1 12.7 14.0 163 >>10 >>10 83 (<10% inhibition (<10% inhibition at 10 μM) at 10 μM)11 >>10 >>10 44 (<10% inhibition (<25% inhibition at 10 μM) at 10 μM) 17for the for the 7 racemate: 6.06 racemate: 9.95 23 for the for the 29racemate: >>10 racemate: >>10 (<10% inhibition (<25% inhibition at 10μM) at 10 μM) 30 17.2  5.93 10 31 >>10 >>10 22 (<10% inhibition (<10%inhibition at 10 μM) at 10 μM)hERG Inhibition Assay

The human Ether-a-go-go Related Gene (hERG) encodes the inwardrectifying voltage gated potassium channel in the heart (I_(Kr)) whichis involved in cardiac repolarisation. I_(Kr) current inhibition hasbeen shown to elongate the cardiac action potential, a phenomenonassociated with increased risk of arrhythmia. I_(Kr) current inhibitionaccounts for the vast majority of known cases of drug-inducedQT-prolongation. A number of drugs have been withdrawn from late stageclinical trials due to these cardiotoxic effects, therefore it isimportant to identify inhibitors early in drug discovery.

The hERG inhibition study aims at quantifying the in vitro effects ofcompounds of the invention on the potassium-selective IK_(r) currentgenerated in normoxic conditions in stably transfected HEK 293 cellswith the human ether-a-go-go-related gene (hERG).

Whole-cell currents (acquisition by manual patch-clamp) elicited duringa voltage pulse were recorded in baseline conditions and followingapplication of tested compounds (5 minutes of exposure). Theconcentrations of tested compounds (0.3 μM; 3 μM; 10 μM; 30 μM) reflecta range believed to exceed the concentrations at expected efficacy dosesin preclinical models.

The pulses protocol applied is described as follow: the holdingpotential (every 3 seconds) was stepped from −80 mV to a maximum valueof +40 mV, starting with −40 mV, in eight increments of +10 mV, for aperiod of 1 second. The membrane potential was then returned to −55 mV,after each of these incremented steps, for 1 second and finallyrepolarized to −80 mV for 1 second.

The current density recorded were normalized against the baselineconditions and corrected for solvent effect and time-dependent currentrun-down using experimental design in test compound free conditions.

Inhibition curves were obtained for compounds and the concentrationswhich decreased 50% of the current density determined in the baselineconditions (IC₅₀) were determined. All compounds for which the IC₅₀value is above 10 M are not considered to be potent inhibitors of thehERG channel whereas compounds with IC₅₀ values below 1 μM areconsidered potent hERG channel inhibitors.

When tested in the hERG inhibition assay, compounds of the inventionwere determined to have IC₅₀ values as shown in Table 8.

TABLE 8 Compound no IC₅₀ (μM) 1 >30 2 >30 3 26 4 >30 11 >30 19 17 22 1229 25 31 20In Vivo Assay to Assess Compound Activity in Rat

The effect of compounds of the invention to inhibit luteinizing hormone(LH) secretion and decrease circulating androgen levels are determinedby the following biological studies.

Castrated Male Rat Model to Assess the Effect of Compound of Inventionon Circulating Levels of Luteinizing Hormone (LH).

In humans and rodents, castration is well-precedented to permitheightened, persistent GnRH signaling and consequent elevation ofcirculating LH. Thus, a castrated rat model is used to provide a broadindex for measurement of LH inhibition as a marker of test compoundinhibition of the GnRH signaling pathway.

Castrated adult male Sprague-Dawley (SD) rats (150-175 g,) werepurchased from Janvier (St Berthevin, France). All animals were housed 3per cage in a temperature-controlled room (22±2° C.) and 50±5% relativehumidity with a 12 hour light/12 hour dark photoperiod (lights off at 6h00 μm). The animals were allowed 2 weeks of postoperative recoveryprior to study. Animals were handled on a daily basis. Standard diet andtap water were provided ad libitum. Animal cage litters were changedonce a week. On the study day, animals were acclimated to the procedureroom for a period of one hour prior to the initiation of the experiment.

Compounds of the invention were formulated as apyrogen water with 90 g/L(2-Hydroxypropyl)-β-CycloDextrin.

After basal sampling (T0) a single dose of compounds of the invention orvehicle was administrated intravenously to rats. Blood was thencollected at 60 min post dosing. Blood samples were obtained via tailvein bleed, drawn into EDTA-containing tubes and centrifugedimmediately. Plasma samples were collected and stored in a −80° C.freezer until assayed. Serum LH levels were determined usingradioimmunoassay kit from RIAZEN—Rat LH, Zentech (Liège, Belgium).Baseline was defined as the initial basal blood sample.

When tested in the castrated male rat model described above, thecompound no. 1 significantly suppressed circulating LH levels (FIG. 3).

When tested in the castrated male rat model described above, thecompound no. 19 significantly suppressed circulating LH levels (FIG. 4).

Gonad-Intact Adult Male to Assess the Effect of Compounds of theInvention on Circulating Levels of Testosterone.

Gonad-intact adult male Sprague-Dawley (SD) rats (225-385 g N=3/groupwere housed in a temperature-controlled room (22±2° C.) and 50±5%relative humidity with a 12 hour light/12 hour dark photoperiod (lightsoff at 6 h00 μm). Rat chow and tap water were made available to rats, adlibitum. After basal blood sampling, free-moving rats were intravenouslyinjected at time=0 min with either a single dose of compound or vehicle.Blood was then collected at times 1, 5, 15, 90, 150, 210 min into tubescontaining EDTA as anticoagulant and centrifuged immediately. Plasmasamples were collected and stored in a −80° C. freezer until assayed.Plasma testosterone levels were determined using a radioimmunoassay kit(Immunotech).

Compound no. 1 was formulated in 9% 2-hydroxypropyl-β-cyclodextrin/H2O(w/w). A single dose of 50 mg/kg of compound no. 1 was intravenouslyinjected.

When tested in gonad-intact male rats, compound no. 1 significantlysuppressed plasma testosterone levels over the 210 minute test period(FIG. 5).

The invention claimed is:
 1. A compound of Formula III

or salts or solvates thereof, wherein the solid line with a starindicates that the individual enantiomers are meant, excluding racemicmixtures thereof; R^(1′) is linear or branched C1-C4 alkyl or C3-C4cycloalkyl, each of said alkyl or cycloakyl groups, groups beingoptionally substituted by one or more group(s) selected from halo oresters; Ar^(2′) is of general Formula (i), (ii) or (iii):

wherein X¹ is N or C—R⁶ wherein R⁶ is H, fluoro or methyl; X² is O or S;X³ is N, or X³ is CH under the condition that X¹ is N and X² is N—R⁷wherein R⁷ is linear or branched C1-C3 alkyl or cyclopropyl; R^(2′) islinear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or branchedC2-C3 alkenyl, C3-C4 cycloalkyl, di(C1-C2 alkyl)amino, phenyl,4-fluorophenyl, 2,4-difluorophenyl or N-morpholinyl; X⁴ is N or C—R⁸wherein R⁸ is H or C1-C2 alkyl, X⁵ is O or S, X⁶ is N or X⁶ is CH underthe condition that X⁴ is N and X⁵ is N—R⁹ wherein R⁹ is C1-C2 alkyl orC3 alkyl or C3 cycloalkyl, or X⁴ is N, X⁵ is N—R⁹ wherein R⁹ is methyland X⁶ is CH; R^(3′) is linear or branched C1-C4 alkyl, C1-C2 haloalkyl,linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl, di(C1-C2alkyl)amino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl orN-morpholinyl; R^(4′) is cyano, C2 alkyl or hydroxyl; R¹¹ is H or anN-sp³ protective group; with the proviso that the compound of FormulaIII is not(R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazolehydrochloride,(R)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazolehydrochloride salt,(S)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,(S)-4-(4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine.2. The compound of claim 1 or a salt or solvate thereof, wherein R¹¹ isH or

wherein R¹², R^(12′), R¹³, R^(13′) and R¹⁴ are H, or R¹⁴ is methoxy andR¹², R^(12′), R¹³ and R¹³ are H, or R¹² and R¹⁴ are methoxy and R^(12′),R¹³ and R^(13′) are H, or R¹², R^(12′) and R¹⁴ are methoxy and R¹³ andR^(13′) are H; and R^(1′) and Ar^(2′) are as defined in claim
 1. 3. Thecompound of claim 1, wherein R^(1′) is C1-C2 alkyl optionallysubstituted by one ester group.
 4. The compound of claim 1 selected fromthe group consisting of Compd n° Structure Chemical name 1

(R)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 2

(S)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 3

(R)-2-ethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 4

(S)-2-ethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 5

(R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole 6

(S)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole 7

(R)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 8

(S)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 9

(R)-2-isopropyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 10

(S)-2-isopropyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 11

(R)-2-cyclopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 12

(S)-2-cyclopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 13

(R)-2,5-dimethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 14

(S)-2,5-dimethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 15

(R)-N,N-dimethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-amine 16

(S)-N,N-dimethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-amine 17

(R)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 18

(S)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 19

(R)-4,5-dimethyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 20

(S)-4,5-dimethyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole 21

(R)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole 22

(S)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole 23

(R)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole 24

(S)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole 25

(R)-3-isopropyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole 26

(S)-3-isopropyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole 27

(R)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 28

(S)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole 29

(R)-3-(1,3-dimethyl-1H-pyrazol-5-yl)- 8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 30

(S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)- 8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 33

(R)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol 34

(S)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-ol 35

(R)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)picolinonitrile 36

(S)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)picolinonitrile 37

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methylthiazole 38

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methylthiazole 39

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- ethylthiazole 40

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- ethylthiazole 41

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole 42

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole 43

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methyloxazole 44

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methyloxazole 45

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- isopropyloxazole 46

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- isopropyloxazole 47

(R)-2-cyclopropyl-4-(7-(2,4- dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole 48

(S)-2-cyclopropyl-4-(7-(2,4- dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole 49

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,5- dimethylthiazole 50

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,5- dimethylthiazole 51

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)- N,N-dimethylthiazol-2-amine 52

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)- N,N-dimethylthiazol-2-amine 53

(R)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methylthiazole 54

(S)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methylthiazole 55

(R)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4,5- dimethylthiazole 56

(S)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4,5- dimethylthiazole 57

(R)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-oxadiazole 58

(S)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-oxadiazole 59

(R)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-thiadiazole 60

(S)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-thiadiazole 61

(R)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- isopropyl-1,2,4-thiadiazole 62

(S)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- isopropyl-1,2,4-thiadiazole 63

(R)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methyloxazole 64

(S)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methyloxazole 65

(R)-7-(2,4-dimethoxybenzyl)-3-(1,3- dimethyl-1H-pyrazol-5-yl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 66

(S)-7-(2,4-dimethoxybenzyl)-3-(1,3- dimethyl-1H-pyrazol-5-yl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine 69

(R)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3- yl)pyridin-2-ol 70

(S)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3- yl)pyridin-2-ol 71

(R)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3- yl)picolinonitrile 72

(S)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3- yl)picolinonitrile 73

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- (4-fluorophenyl)thiazole 74

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- (4-fluorophenyl)thiazole.


5. A compound according to claim 1, or a salt or solvate thereof, asintermediate for the synthesis of a pharmaceutical active ingredient.